ICYMI Multiple Sclerosis

The modified Story Memory Technique (mSMT), a behavioral intervention aimed at improving new learning and memory in patients with multiple sclerosis, may help with processing speed and other cognitive markers, according to the double-blind, placebo-controlled, MEMREHAB trial of patients with clinically definite multiple sclerosis.

Participants were randomized to either mSMT or a placebo group, and underwent baseline and follow-up neuropsychological assessment. Compared to the control group, the treatment group showed significant improvements on California Verbal Learning Test (CVLT).

Investigators also note that performance on the Symbol Digit Modalities Test (SDMT) was a significant predictor of benefit from mSMT therapy, suggesting SDMT scores may serve as a proxy for overall cognitive impairment.

Citation: Chiaravalloti ND, DeLuca J. The influence of cognitive dysfunction on benefit from learning and memory rehabilitation in MS: a sub-analysis of the MEMREHAB trial. Mult Scler. 2015. pii: 1352458514567726.

The modified Story Memory Technique (mSMT), a behavioral intervention aimed at improving new learning and memory in patients with multiple sclerosis, may help with processing speed and other cognitive markers, according to the double-blind, placebo-controlled, MEMREHAB trial of patients with clinically definite multiple sclerosis.

Participants were randomized to either mSMT or a placebo group, and underwent baseline and follow-up neuropsychological assessment. Compared to the control group, the treatment group showed significant improvements on California Verbal Learning Test (CVLT).

Investigators also note that performance on the Symbol Digit Modalities Test (SDMT) was a significant predictor of benefit from mSMT therapy, suggesting SDMT scores may serve as a proxy for overall cognitive impairment.

Citation: Chiaravalloti ND, DeLuca J. The influence of cognitive dysfunction on benefit from learning and memory rehabilitation in MS: a sub-analysis of the MEMREHAB trial. Mult Scler. 2015. pii: 1352458514567726.

The modified Story Memory Technique (mSMT), a behavioral intervention aimed at improving new learning and memory in patients with multiple sclerosis, may help with processing speed and other cognitive markers, according to the double-blind, placebo-controlled, MEMREHAB trial of patients with clinically definite multiple sclerosis.

Participants were randomized to either mSMT or a placebo group, and underwent baseline and follow-up neuropsychological assessment. Compared to the control group, the treatment group showed significant improvements on California Verbal Learning Test (CVLT).

Investigators also note that performance on the Symbol Digit Modalities Test (SDMT) was a significant predictor of benefit from mSMT therapy, suggesting SDMT scores may serve as a proxy for overall cognitive impairment.

Citation: Chiaravalloti ND, DeLuca J. The influence of cognitive dysfunction on benefit from learning and memory rehabilitation in MS: a sub-analysis of the MEMREHAB trial. Mult Scler. 2015. pii: 1352458514567726.

Researchers have identified a genetic variation that significantly increases women’s risk of developing multiple sclerosis (MS). The variant, a single nucleotide polymorphism (SNP) in the gene serine-threonine-kinase 11 (STK11), occurs approximately 1.7 times more often in women with MS than in women without the disease, according to a study published February 18 in ASN Neuro.

Researchers zeroed in on the STK11 SNP after a woman told study coordinator and lead author Anne I. Boullerne, PhD, Research Assistant Professor of Anesthesiology at the University of Illinois at Chicago, that she and her four siblings all had MS or clinically isolated syndrome. The five siblings—four sisters, including twins, and a brother—were between ages 23 and 26.

The woman, who was participating in another medical study at the university, also described a prevalence of diseases associated with Peutz–Jeghers syndrome, a rare genetic disease caused by mutations in the STK11 gene, on her mother’s side of the family. The syndrome is characterized by an increased risk for certain cancers, including breast, ovary, and colon cancers.

Gene Tied to Loss of Myelin in Mice
A literature search by senior author Douglas L. Feinstein, PhD, Professor of Anesthesiology at the University of Illinois at Chicago and Research Biologist at the Jesse Brown VA Medical Center, uncovered an article that described how mice with a disabled STK11 gene had a higher incidence of loss of myelin from the nerves of the CNS, a defining characteristic of MS.

The woman consented to a complete DNA sequencing of her genome, and Dr. Boullerne examined the STK11 gene, where she discovered the SNP. Dr. Boullerne then obtained consent to sequence the genomes of two of the woman’s sisters and found that they carried the same SNP. Researchers do not know whether the other two siblings have the same variation.

The authors then screened DNA samples from approximately 1,400 people, including 754 people with MS. They found that the SNP was 1.66 times as prevalent in women with MS as in women without the disease. That makes the variant “one of the strongest genetic risk factors for MS discovered to date,” Dr. Feinstein said.

Researchers compared DNA samples from 654 patients with relapsing-remitting MS (RRMS), 100 patients with primary progressive MS (PPMS), and 661 controls.

While the STK11 SNP is present in about 7% of the general population, the variant was present in approximately 11% of the women with MS. In men, the risk of RRMS was only modestly increased by the STK11 SNP, and none of the male patients with PPMS had the variant.

Variant Associated With Reduced Disease Severity
The STK11 SNP was not associated with disease duration or onset. However, it was significantly associated with reduced disease severity, with the lowest MS severity scores in patients who also harbored the HLA-DRB1*1501 allele, the strongest known genetic risk factor for MS.

The researchers plan to continue looking for other genetic risk factors for MS among the five siblings and possibly their parents. Dr. Boullerne found no published studies that identified five siblings with MS. Identifying the five siblings with MS and suspected MS is an opportunity to pinpoint genes related to the disease, she said.

“I was immediately interested in the possibility of a genetic study of the family because all five siblings—an entire generation—are affected by MS, and so we could have a very good chance of discovering key genes related to inheritance of the disease,” Dr. Boullerne said.

Researchers also will investigate the function of the STK11 gene in the laboratory, which could reveal molecular pathways involved in MS. Their findings raise the possibility that cells harboring the STK11 SNP could be targeted by drugs that increase metabolic stress.

Rarity of Cases Has Limited Analyses
Genetic factors are known to influence the risk of developing MS, but the rarity of multigenerational cases of MS, or families with four or more affected members, has limited further analyses, said the authors.

Several studies have identified the HLA-DRB1*1501 allele as a variant associated with increased risk, with an odds ratio of approximately 3 across various ethnic groups.

The STK11 SNP had odds ratios for females of 1.63 in RRMS, 1.88 in PPMS, and 1.66 for both MS forms.

The different ratios for women with RRMS and PPMS could result from the different group sizes used in the study (ie, 56 female patients with PPMS, compared with 396 female patients with RRMS) or because of differences in the development and evolution of PPMS and RRMS, said the authors.

—Jake Remaly

Researchers have identified a genetic variation that significantly increases women’s risk of developing multiple sclerosis (MS). The variant, a single nucleotide polymorphism (SNP) in the gene serine-threonine-kinase 11 (STK11), occurs approximately 1.7 times more often in women with MS than in women without the disease, according to a study published February 18 in ASN Neuro.

Researchers zeroed in on the STK11 SNP after a woman told study coordinator and lead author Anne I. Boullerne, PhD, Research Assistant Professor of Anesthesiology at the University of Illinois at Chicago, that she and her four siblings all had MS or clinically isolated syndrome. The five siblings—four sisters, including twins, and a brother—were between ages 23 and 26.

The woman, who was participating in another medical study at the university, also described a prevalence of diseases associated with Peutz–Jeghers syndrome, a rare genetic disease caused by mutations in the STK11 gene, on her mother’s side of the family. The syndrome is characterized by an increased risk for certain cancers, including breast, ovary, and colon cancers.

Gene Tied to Loss of Myelin in Mice
A literature search by senior author Douglas L. Feinstein, PhD, Professor of Anesthesiology at the University of Illinois at Chicago and Research Biologist at the Jesse Brown VA Medical Center, uncovered an article that described how mice with a disabled STK11 gene had a higher incidence of loss of myelin from the nerves of the CNS, a defining characteristic of MS.

The woman consented to a complete DNA sequencing of her genome, and Dr. Boullerne examined the STK11 gene, where she discovered the SNP. Dr. Boullerne then obtained consent to sequence the genomes of two of the woman’s sisters and found that they carried the same SNP. Researchers do not know whether the other two siblings have the same variation.

The authors then screened DNA samples from approximately 1,400 people, including 754 people with MS. They found that the SNP was 1.66 times as prevalent in women with MS as in women without the disease. That makes the variant “one of the strongest genetic risk factors for MS discovered to date,” Dr. Feinstein said.

Researchers compared DNA samples from 654 patients with relapsing-remitting MS (RRMS), 100 patients with primary progressive MS (PPMS), and 661 controls.

While the STK11 SNP is present in about 7% of the general population, the variant was present in approximately 11% of the women with MS. In men, the risk of RRMS was only modestly increased by the STK11 SNP, and none of the male patients with PPMS had the variant.

Variant Associated With Reduced Disease Severity
The STK11 SNP was not associated with disease duration or onset. However, it was significantly associated with reduced disease severity, with the lowest MS severity scores in patients who also harbored the HLA-DRB1*1501 allele, the strongest known genetic risk factor for MS.

The researchers plan to continue looking for other genetic risk factors for MS among the five siblings and possibly their parents. Dr. Boullerne found no published studies that identified five siblings with MS. Identifying the five siblings with MS and suspected MS is an opportunity to pinpoint genes related to the disease, she said.

“I was immediately interested in the possibility of a genetic study of the family because all five siblings—an entire generation—are affected by MS, and so we could have a very good chance of discovering key genes related to inheritance of the disease,” Dr. Boullerne said.

Researchers also will investigate the function of the STK11 gene in the laboratory, which could reveal molecular pathways involved in MS. Their findings raise the possibility that cells harboring the STK11 SNP could be targeted by drugs that increase metabolic stress.

Rarity of Cases Has Limited Analyses
Genetic factors are known to influence the risk of developing MS, but the rarity of multigenerational cases of MS, or families with four or more affected members, has limited further analyses, said the authors.

Several studies have identified the HLA-DRB1*1501 allele as a variant associated with increased risk, with an odds ratio of approximately 3 across various ethnic groups.

The STK11 SNP had odds ratios for females of 1.63 in RRMS, 1.88 in PPMS, and 1.66 for both MS forms.

The different ratios for women with RRMS and PPMS could result from the different group sizes used in the study (ie, 56 female patients with PPMS, compared with 396 female patients with RRMS) or because of differences in the development and evolution of PPMS and RRMS, said the authors.

—Jake Remaly

Researchers have identified a genetic variation that significantly increases women’s risk of developing multiple sclerosis (MS). The variant, a single nucleotide polymorphism (SNP) in the gene serine-threonine-kinase 11 (STK11), occurs approximately 1.7 times more often in women with MS than in women without the disease, according to a study published February 18 in ASN Neuro.

Researchers zeroed in on the STK11 SNP after a woman told study coordinator and lead author Anne I. Boullerne, PhD, Research Assistant Professor of Anesthesiology at the University of Illinois at Chicago, that she and her four siblings all had MS or clinically isolated syndrome. The five siblings—four sisters, including twins, and a brother—were between ages 23 and 26.

The woman, who was participating in another medical study at the university, also described a prevalence of diseases associated with Peutz–Jeghers syndrome, a rare genetic disease caused by mutations in the STK11 gene, on her mother’s side of the family. The syndrome is characterized by an increased risk for certain cancers, including breast, ovary, and colon cancers.

Gene Tied to Loss of Myelin in Mice
A literature search by senior author Douglas L. Feinstein, PhD, Professor of Anesthesiology at the University of Illinois at Chicago and Research Biologist at the Jesse Brown VA Medical Center, uncovered an article that described how mice with a disabled STK11 gene had a higher incidence of loss of myelin from the nerves of the CNS, a defining characteristic of MS.

The woman consented to a complete DNA sequencing of her genome, and Dr. Boullerne examined the STK11 gene, where she discovered the SNP. Dr. Boullerne then obtained consent to sequence the genomes of two of the woman’s sisters and found that they carried the same SNP. Researchers do not know whether the other two siblings have the same variation.

The authors then screened DNA samples from approximately 1,400 people, including 754 people with MS. They found that the SNP was 1.66 times as prevalent in women with MS as in women without the disease. That makes the variant “one of the strongest genetic risk factors for MS discovered to date,” Dr. Feinstein said.

Researchers compared DNA samples from 654 patients with relapsing-remitting MS (RRMS), 100 patients with primary progressive MS (PPMS), and 661 controls.

While the STK11 SNP is present in about 7% of the general population, the variant was present in approximately 11% of the women with MS. In men, the risk of RRMS was only modestly increased by the STK11 SNP, and none of the male patients with PPMS had the variant.

Variant Associated With Reduced Disease Severity
The STK11 SNP was not associated with disease duration or onset. However, it was significantly associated with reduced disease severity, with the lowest MS severity scores in patients who also harbored the HLA-DRB1*1501 allele, the strongest known genetic risk factor for MS.

The researchers plan to continue looking for other genetic risk factors for MS among the five siblings and possibly their parents. Dr. Boullerne found no published studies that identified five siblings with MS. Identifying the five siblings with MS and suspected MS is an opportunity to pinpoint genes related to the disease, she said.

“I was immediately interested in the possibility of a genetic study of the family because all five siblings—an entire generation—are affected by MS, and so we could have a very good chance of discovering key genes related to inheritance of the disease,” Dr. Boullerne said.

Researchers also will investigate the function of the STK11 gene in the laboratory, which could reveal molecular pathways involved in MS. Their findings raise the possibility that cells harboring the STK11 SNP could be targeted by drugs that increase metabolic stress.

Rarity of Cases Has Limited Analyses
Genetic factors are known to influence the risk of developing MS, but the rarity of multigenerational cases of MS, or families with four or more affected members, has limited further analyses, said the authors.

Several studies have identified the HLA-DRB1*1501 allele as a variant associated with increased risk, with an odds ratio of approximately 3 across various ethnic groups.

The STK11 SNP had odds ratios for females of 1.63 in RRMS, 1.88 in PPMS, and 1.66 for both MS forms.

The different ratios for women with RRMS and PPMS could result from the different group sizes used in the study (ie, 56 female patients with PPMS, compared with 396 female patients with RRMS) or because of differences in the development and evolution of PPMS and RRMS, said the authors.

—Jake Remaly

A new research initiative for multiple sclerosis (MS) is seeking to recruit 20,000 people with MS—about 5% of the estimated US population with the disease—by this September, and aims to change the way MS research is conducted.

The web-based initiative, called iConquerMS, was formed with the help of a nearly $1-million contract from the Patient-Centered Outcomes Research Institute set up under the Affordable Care Act of 2010. iConquerMS is led by the Accelerated Cure Project for MS, a nonprofit research organization based in Waltham, Massachusetts.

Among the group’s initiatives is OPT-UP, a five-year, clinic-based study designed to compare patient outcomes from all the approved MS treatments and develop the evidence base for personalized medicine for MS. iConquerMS grew out of Accelerated Cure’s large-scale biospecimen and data repository, as well as the planning phase of OPT-UP, said Robert McBurney, PhD, the CEO of Accelerated Cure and the principal investigator for iConquerMS.

“Patients recruited into OPT-UP could become part of iConquerMS. But OPT-UP seeks only 2,500 patients,” Dr. McBurney said, “while iConquerMS is soliciting participation from a much larger number of MS patients, along with other participants, such as friends and relatives of people with MS, who want to contribute their data.”

The combination of the registry and OPT-UP “gives us the pathway to start a very long-term study of MS,” Dr. McBurney said. “Perhaps the children of people with MS will sign up as well. OPT-UP plus iConquerMS really has the possibility of becoming the Framingham of MS.” To date, iConquerMS has enrolled about 1,000 participants who are encouraged to contribute their health information through surveys and electronic health records.

New Registry Joins Several Existing MS Patient Registries
iConquerMS joins a handful of existing MS patient registries, including the 20-year-old North American Research Committee on MS (NARCOMS), a nonprofit registry with more than 36,000 patients, and the newly established North American Registry for Care and Research in MS (NARCRMS). Patients Like Me, a for-profit registry founded in 2004 for people with chronic diseases, now counts about 38,000 members with MS.

June Halper, CEO of the Hackensack, New Jersey-based Consortium of MS Centers (CMSC), which administers NARCOMS and NARCRMS, said that while there is some sense of competition among the MS registries, there should be no dearth of patients to enroll and many opportunities to collaborate.

“We hope that not too far into this picture we will be able to work with iConquerMS,” she said, “because the more we know about MS from the patient’s perspective, the better it’s going to be. One of the things we don’t have is any kind of comparative study comparing outcomes of one disease-modifying drug to another, and OPT-UP is seeking to do that, which is very important,” she added.

Ms. Halper said that in 1995, when the NARCOMS registry was established, “all we could do was symptomatic management, and we could treat relapses, but there were no disease-modifying therapies. We didn’t have MRI. We had rehab but we didn’t know much about it. People with MS were told to rest a lot by their neurologists.”

The NARCOMS surveys—now mostly online—were conducted then as mailed questionnaires. Deidentified patient-reported data from NARCOMS have since generated dozens of papers with findings on smoking, vitamin D, reproduction, depression, fatigue, comorbidities, and other subjects.

Dr. McBurney noted that the patient-centric approach is consistent with broader trends in MS clinical research favoring more nuanced measures of patient outcomes “well beyond MRI and the 25-foot walk,” he said. “These don’t capture the whole experience, and it’s important to incorporate the patient voice in outcome measures.”

NARCOMS relies exclusively on patient-reported information. The registry does not draw on medical records or validation of disease status, though one study found that virtually all NARCOMS participants have an MS diagnosis, Ms. Halper said. Patients Like Me is similarly reliant on patient-reported data.

Patient- and Physician-Reported Information
The two new initiatives, iConquerMS and NARCRMS, differ from prior registries in that they add a significant component of physician-reported data to complement the patient portal. iConquerMS, for example, requests submission of electronic health records. “The anchor of the electronic health record is helpful to confirm some of the information contributed by the patient, but the most important part is patient-reported health information,” Dr. McBurney said.

NARCRMS—launched as a complement to NARCOMS—focuses as much on physician reports as patient reports to create “a concurrent longitudinal database that simultaneously captures both patient-based and physician-based information,” according to its website. The site, which also will incorporate imaging data, is modeled closely after an open-access Alzheimer’s disease database—the Alzheimer’s Disease Neuroimaging Initiative. Participating patients will be able to access the database to see how they compare with others.

Industry participation varies among the registries. NARCOMS does not receive money from industry except for use in selected studies, while Patients Like Me sells deidentified patient data to pharmaceutical and device manufacturers. NARCRMS allows its industry sponsors full access to its data, and iConquerMS has also received industry support.

More Data Yield More Answers
The proliferation of registries should bring MS research closer to that seen with other chronic diseases, said Ms. Halper. While people are being diagnosed more quickly, and more treatments are available, there is still a lot of work to be done, she said. “We don’t know a heck of a lot about MS, and everybody wants to know more. We need data.”

Dr. McBurney concurred. “We’re making an impact on the early relapsing-remitting phase of the disorder, but to date, no drugs have been approved for progressive MS. Maybe they’re not even the same disease. We still have very little idea which patient is going to benefit from any particular treatment strategy without experiencing troubling side effects,” he said. Registry data may help answer these and other questions.

—Jennie Smith

A new research initiative for multiple sclerosis (MS) is seeking to recruit 20,000 people with MS—about 5% of the estimated US population with the disease—by this September, and aims to change the way MS research is conducted.

The web-based initiative, called iConquerMS, was formed with the help of a nearly $1-million contract from the Patient-Centered Outcomes Research Institute set up under the Affordable Care Act of 2010. iConquerMS is led by the Accelerated Cure Project for MS, a nonprofit research organization based in Waltham, Massachusetts.

Among the group’s initiatives is OPT-UP, a five-year, clinic-based study designed to compare patient outcomes from all the approved MS treatments and develop the evidence base for personalized medicine for MS. iConquerMS grew out of Accelerated Cure’s large-scale biospecimen and data repository, as well as the planning phase of OPT-UP, said Robert McBurney, PhD, the CEO of Accelerated Cure and the principal investigator for iConquerMS.

“Patients recruited into OPT-UP could become part of iConquerMS. But OPT-UP seeks only 2,500 patients,” Dr. McBurney said, “while iConquerMS is soliciting participation from a much larger number of MS patients, along with other participants, such as friends and relatives of people with MS, who want to contribute their data.”

The combination of the registry and OPT-UP “gives us the pathway to start a very long-term study of MS,” Dr. McBurney said. “Perhaps the children of people with MS will sign up as well. OPT-UP plus iConquerMS really has the possibility of becoming the Framingham of MS.” To date, iConquerMS has enrolled about 1,000 participants who are encouraged to contribute their health information through surveys and electronic health records.

New Registry Joins Several Existing MS Patient Registries
iConquerMS joins a handful of existing MS patient registries, including the 20-year-old North American Research Committee on MS (NARCOMS), a nonprofit registry with more than 36,000 patients, and the newly established North American Registry for Care and Research in MS (NARCRMS). Patients Like Me, a for-profit registry founded in 2004 for people with chronic diseases, now counts about 38,000 members with MS.

June Halper, CEO of the Hackensack, New Jersey-based Consortium of MS Centers (CMSC), which administers NARCOMS and NARCRMS, said that while there is some sense of competition among the MS registries, there should be no dearth of patients to enroll and many opportunities to collaborate.

“We hope that not too far into this picture we will be able to work with iConquerMS,” she said, “because the more we know about MS from the patient’s perspective, the better it’s going to be. One of the things we don’t have is any kind of comparative study comparing outcomes of one disease-modifying drug to another, and OPT-UP is seeking to do that, which is very important,” she added.

Ms. Halper said that in 1995, when the NARCOMS registry was established, “all we could do was symptomatic management, and we could treat relapses, but there were no disease-modifying therapies. We didn’t have MRI. We had rehab but we didn’t know much about it. People with MS were told to rest a lot by their neurologists.”

The NARCOMS surveys—now mostly online—were conducted then as mailed questionnaires. Deidentified patient-reported data from NARCOMS have since generated dozens of papers with findings on smoking, vitamin D, reproduction, depression, fatigue, comorbidities, and other subjects.

Dr. McBurney noted that the patient-centric approach is consistent with broader trends in MS clinical research favoring more nuanced measures of patient outcomes “well beyond MRI and the 25-foot walk,” he said. “These don’t capture the whole experience, and it’s important to incorporate the patient voice in outcome measures.”

NARCOMS relies exclusively on patient-reported information. The registry does not draw on medical records or validation of disease status, though one study found that virtually all NARCOMS participants have an MS diagnosis, Ms. Halper said. Patients Like Me is similarly reliant on patient-reported data.

Patient- and Physician-Reported Information
The two new initiatives, iConquerMS and NARCRMS, differ from prior registries in that they add a significant component of physician-reported data to complement the patient portal. iConquerMS, for example, requests submission of electronic health records. “The anchor of the electronic health record is helpful to confirm some of the information contributed by the patient, but the most important part is patient-reported health information,” Dr. McBurney said.

NARCRMS—launched as a complement to NARCOMS—focuses as much on physician reports as patient reports to create “a concurrent longitudinal database that simultaneously captures both patient-based and physician-based information,” according to its website. The site, which also will incorporate imaging data, is modeled closely after an open-access Alzheimer’s disease database—the Alzheimer’s Disease Neuroimaging Initiative. Participating patients will be able to access the database to see how they compare with others.

Industry participation varies among the registries. NARCOMS does not receive money from industry except for use in selected studies, while Patients Like Me sells deidentified patient data to pharmaceutical and device manufacturers. NARCRMS allows its industry sponsors full access to its data, and iConquerMS has also received industry support.

More Data Yield More Answers
The proliferation of registries should bring MS research closer to that seen with other chronic diseases, said Ms. Halper. While people are being diagnosed more quickly, and more treatments are available, there is still a lot of work to be done, she said. “We don’t know a heck of a lot about MS, and everybody wants to know more. We need data.”

Dr. McBurney concurred. “We’re making an impact on the early relapsing-remitting phase of the disorder, but to date, no drugs have been approved for progressive MS. Maybe they’re not even the same disease. We still have very little idea which patient is going to benefit from any particular treatment strategy without experiencing troubling side effects,” he said. Registry data may help answer these and other questions.

—Jennie Smith

A new research initiative for multiple sclerosis (MS) is seeking to recruit 20,000 people with MS—about 5% of the estimated US population with the disease—by this September, and aims to change the way MS research is conducted.

The web-based initiative, called iConquerMS, was formed with the help of a nearly $1-million contract from the Patient-Centered Outcomes Research Institute set up under the Affordable Care Act of 2010. iConquerMS is led by the Accelerated Cure Project for MS, a nonprofit research organization based in Waltham, Massachusetts.

Among the group’s initiatives is OPT-UP, a five-year, clinic-based study designed to compare patient outcomes from all the approved MS treatments and develop the evidence base for personalized medicine for MS. iConquerMS grew out of Accelerated Cure’s large-scale biospecimen and data repository, as well as the planning phase of OPT-UP, said Robert McBurney, PhD, the CEO of Accelerated Cure and the principal investigator for iConquerMS.

“Patients recruited into OPT-UP could become part of iConquerMS. But OPT-UP seeks only 2,500 patients,” Dr. McBurney said, “while iConquerMS is soliciting participation from a much larger number of MS patients, along with other participants, such as friends and relatives of people with MS, who want to contribute their data.”

The combination of the registry and OPT-UP “gives us the pathway to start a very long-term study of MS,” Dr. McBurney said. “Perhaps the children of people with MS will sign up as well. OPT-UP plus iConquerMS really has the possibility of becoming the Framingham of MS.” To date, iConquerMS has enrolled about 1,000 participants who are encouraged to contribute their health information through surveys and electronic health records.

New Registry Joins Several Existing MS Patient Registries
iConquerMS joins a handful of existing MS patient registries, including the 20-year-old North American Research Committee on MS (NARCOMS), a nonprofit registry with more than 36,000 patients, and the newly established North American Registry for Care and Research in MS (NARCRMS). Patients Like Me, a for-profit registry founded in 2004 for people with chronic diseases, now counts about 38,000 members with MS.

June Halper, CEO of the Hackensack, New Jersey-based Consortium of MS Centers (CMSC), which administers NARCOMS and NARCRMS, said that while there is some sense of competition among the MS registries, there should be no dearth of patients to enroll and many opportunities to collaborate.

“We hope that not too far into this picture we will be able to work with iConquerMS,” she said, “because the more we know about MS from the patient’s perspective, the better it’s going to be. One of the things we don’t have is any kind of comparative study comparing outcomes of one disease-modifying drug to another, and OPT-UP is seeking to do that, which is very important,” she added.

Ms. Halper said that in 1995, when the NARCOMS registry was established, “all we could do was symptomatic management, and we could treat relapses, but there were no disease-modifying therapies. We didn’t have MRI. We had rehab but we didn’t know much about it. People with MS were told to rest a lot by their neurologists.”

The NARCOMS surveys—now mostly online—were conducted then as mailed questionnaires. Deidentified patient-reported data from NARCOMS have since generated dozens of papers with findings on smoking, vitamin D, reproduction, depression, fatigue, comorbidities, and other subjects.

Dr. McBurney noted that the patient-centric approach is consistent with broader trends in MS clinical research favoring more nuanced measures of patient outcomes “well beyond MRI and the 25-foot walk,” he said. “These don’t capture the whole experience, and it’s important to incorporate the patient voice in outcome measures.”

NARCOMS relies exclusively on patient-reported information. The registry does not draw on medical records or validation of disease status, though one study found that virtually all NARCOMS participants have an MS diagnosis, Ms. Halper said. Patients Like Me is similarly reliant on patient-reported data.

Patient- and Physician-Reported Information
The two new initiatives, iConquerMS and NARCRMS, differ from prior registries in that they add a significant component of physician-reported data to complement the patient portal. iConquerMS, for example, requests submission of electronic health records. “The anchor of the electronic health record is helpful to confirm some of the information contributed by the patient, but the most important part is patient-reported health information,” Dr. McBurney said.

NARCRMS—launched as a complement to NARCOMS—focuses as much on physician reports as patient reports to create “a concurrent longitudinal database that simultaneously captures both patient-based and physician-based information,” according to its website. The site, which also will incorporate imaging data, is modeled closely after an open-access Alzheimer’s disease database—the Alzheimer’s Disease Neuroimaging Initiative. Participating patients will be able to access the database to see how they compare with others.

Industry participation varies among the registries. NARCOMS does not receive money from industry except for use in selected studies, while Patients Like Me sells deidentified patient data to pharmaceutical and device manufacturers. NARCRMS allows its industry sponsors full access to its data, and iConquerMS has also received industry support.

More Data Yield More Answers
The proliferation of registries should bring MS research closer to that seen with other chronic diseases, said Ms. Halper. While people are being diagnosed more quickly, and more treatments are available, there is still a lot of work to be done, she said. “We don’t know a heck of a lot about MS, and everybody wants to know more. We need data.”

Dr. McBurney concurred. “We’re making an impact on the early relapsing-remitting phase of the disorder, but to date, no drugs have been approved for progressive MS. Maybe they’re not even the same disease. We still have very little idea which patient is going to benefit from any particular treatment strategy without experiencing troubling side effects,” he said. Registry data may help answer these and other questions.

—Jennie Smith

NAPLES, FLORIDA—Psychiatric comorbidities, particularly depression, worsen the course of major neurologic conditions, according to research described at the 42nd Annual Meeting of the Southern Clinical Neurological Society. Among individuals with neurologic diseases, depression is associated with greater cognitive deficits, greater impairments in activities of daily living, and lower quality of life.

“Intuitively, we would think that if we treat those comorbid depressive disorders, patients’ course would get better,” said Andres M. Kanner, MD, Professor of Clinical Neurology at the University of Miami Miller School of Medicine. “The problem is that there’s been such apathy about paying attention to comorbid depressive disorders in neurologic conditions that there are no good data on their treatment.” This lack of data needs to be addressed, he added.

A Bidirectional Relationship
The pathogenic mechanisms operant in the development of mood disorders include environmental factors (eg, stressful events), genetic predispositions, and neurotransmitter and neuroendocrine disturbances, which, in turn, can result in structural and functional changes in the CNS. These changes could explain why the course of a neurologic condition is worse among patients with depression than among patients without depression.

Various studies have suggested that depression and some neurologic disorders share common pathogenic mechanisms. For example, data indicate that decreased binding of the serotonin 1A receptor in the hippocampus, insula, amygdala, cingulate gyrus, and Raphe nuclei occurs in temporal lobe epilepsy and depression. Depression also is associated with low platelet serotonin concentration, which can yield a higher platelet adhesivity, and increased secretion of cytokines, which may be associated with vasculitic processes. These factors may heighten the risk of stroke. Likewise, glutamate, one of the neurotransmitters implicated in epileptogenesis, is present at high levels in the CSF, plasma, and cortex of patients with depression.

Depression is common among patients with neurologic disorders. Population-based studies suggest that one in every three patients who develop stroke, epilepsy, migraine, or Parkinson’s disease will develop depression. Between 27% and 54% of patients with multiple sclerosis (MS) have had an episode of major depressive disorder. And between 30% and 50% of patients with dementia have depression.

Depression and neurologic disorders appear to have a bidirectional relationship. “Not only are people with some of the major neurologic conditions more likely to develop depression, but a history of depression is associated with a higher risk of developing several of the neurologic conditions, such as epilepsy, migraine, stroke, Parkinson’s disease, and dementia,” said Dr. Kanner. This complex interaction also affects clinical treatment. A patient’s family psychiatric history, psychiatric comorbidity, and stressful life events can influence his or her response to pharmacotherapy, as well as the development of psychiatric adverse events to pharmacologic and surgical treatment.

Depression’s Effects in Neurologic Diseases
The negative effects of mood disorders vary according to the patient’s neurologic disease. Researchers at Johns Hopkins University found that patients with stroke and major poststroke depression had significantly more cognitive deficits than patients with stroke who did not have depression. In a follow-up study, the same researchers found that major poststroke depression was associated with greater cognitive impairment at two years after stroke onset. A separate investigation indicated that in-hospital poststroke depression was the most important predictor of poor recovery in activities of daily living after two years. Other data suggested that mortality risk was 50% higher for patients with stroke and poststroke depression than for patients with stroke without poststroke depression.

Among people with MS, depression significantly and independently affects quality of life. In one trial, depression was a stronger predictor of poor quality of life than disease severity, as measured by the Expanded Disability Status Scale. A study of 136 patients with MS found that depression decreased quality of life by reducing energy, mental health, sexual function, and cognitive function.

Among people with Alzheimer’s dementia, depression is a predictor of cognitive decline and is associated with greater impairment in activities of daily living. For this population, depression also is associated with an earlier need for placement in a nursing home, an earlier need for transfer from an assisted-living facility to a higher-level health care facility, and increased caregiver depression and burden.

In addition, depression is the factor most closely related to poor quality of life among patients with Parkinson’s disease. “Depression in Parkinson’s disease has been associated with a more rapid deterioration of motor and cognitive function, especially executive function, and a greater likelihood of displaying psychotic symptoms and physical disability,” said Dr. Kanner. In people with Parkinson’s disease, depression is associated with impairment in set shifting and concept formation.

Depression Complicates Epilepsy Treatment
Several studies describe the various negative effects that depression has among people with epilepsy. Investigators in the United Kingdom concluded that people with a lifetime history of depression before epilepsy onset were twice as likely to develop treatment-resistant epilepsy than people without depression before epilepsy onset.

In an Australian study of people with new-onset epilepsy, comorbid symptoms of depression and anxiety at epilepsy diagnosis were associated with a lower likelihood of being seizure-free at 52 weeks of treatment. Research by Dr. Kanner and colleagues found that among patients who became seizure-free after temporal lobectomy, 12% had had a lifetime history of depression. Approximately 80% of people who had resistant seizures after surgery had had a lifetime history of depression.

A multicenter study of people with epilepsy indicated that patients with depression or anxiety were significantly more likely to have a greater number and severity of adverse events from antiepileptic drugs. Other data indicate a high correlation between severity of depression and poor quality of life among individuals with treatment-resistant temporal lobe epilepsy. This investigation also found no correlation between seizure frequency and quality of life.

—Erik Greb

NAPLES, FLORIDA—Psychiatric comorbidities, particularly depression, worsen the course of major neurologic conditions, according to research described at the 42nd Annual Meeting of the Southern Clinical Neurological Society. Among individuals with neurologic diseases, depression is associated with greater cognitive deficits, greater impairments in activities of daily living, and lower quality of life.

“Intuitively, we would think that if we treat those comorbid depressive disorders, patients’ course would get better,” said Andres M. Kanner, MD, Professor of Clinical Neurology at the University of Miami Miller School of Medicine. “The problem is that there’s been such apathy about paying attention to comorbid depressive disorders in neurologic conditions that there are no good data on their treatment.” This lack of data needs to be addressed, he added.

A Bidirectional Relationship
The pathogenic mechanisms operant in the development of mood disorders include environmental factors (eg, stressful events), genetic predispositions, and neurotransmitter and neuroendocrine disturbances, which, in turn, can result in structural and functional changes in the CNS. These changes could explain why the course of a neurologic condition is worse among patients with depression than among patients without depression.

Various studies have suggested that depression and some neurologic disorders share common pathogenic mechanisms. For example, data indicate that decreased binding of the serotonin 1A receptor in the hippocampus, insula, amygdala, cingulate gyrus, and Raphe nuclei occurs in temporal lobe epilepsy and depression. Depression also is associated with low platelet serotonin concentration, which can yield a higher platelet adhesivity, and increased secretion of cytokines, which may be associated with vasculitic processes. These factors may heighten the risk of stroke. Likewise, glutamate, one of the neurotransmitters implicated in epileptogenesis, is present at high levels in the CSF, plasma, and cortex of patients with depression.

Depression is common among patients with neurologic disorders. Population-based studies suggest that one in every three patients who develop stroke, epilepsy, migraine, or Parkinson’s disease will develop depression. Between 27% and 54% of patients with multiple sclerosis (MS) have had an episode of major depressive disorder. And between 30% and 50% of patients with dementia have depression.

Depression and neurologic disorders appear to have a bidirectional relationship. “Not only are people with some of the major neurologic conditions more likely to develop depression, but a history of depression is associated with a higher risk of developing several of the neurologic conditions, such as epilepsy, migraine, stroke, Parkinson’s disease, and dementia,” said Dr. Kanner. This complex interaction also affects clinical treatment. A patient’s family psychiatric history, psychiatric comorbidity, and stressful life events can influence his or her response to pharmacotherapy, as well as the development of psychiatric adverse events to pharmacologic and surgical treatment.

Depression’s Effects in Neurologic Diseases
The negative effects of mood disorders vary according to the patient’s neurologic disease. Researchers at Johns Hopkins University found that patients with stroke and major poststroke depression had significantly more cognitive deficits than patients with stroke who did not have depression. In a follow-up study, the same researchers found that major poststroke depression was associated with greater cognitive impairment at two years after stroke onset. A separate investigation indicated that in-hospital poststroke depression was the most important predictor of poor recovery in activities of daily living after two years. Other data suggested that mortality risk was 50% higher for patients with stroke and poststroke depression than for patients with stroke without poststroke depression.

Among people with MS, depression significantly and independently affects quality of life. In one trial, depression was a stronger predictor of poor quality of life than disease severity, as measured by the Expanded Disability Status Scale. A study of 136 patients with MS found that depression decreased quality of life by reducing energy, mental health, sexual function, and cognitive function.

Among people with Alzheimer’s dementia, depression is a predictor of cognitive decline and is associated with greater impairment in activities of daily living. For this population, depression also is associated with an earlier need for placement in a nursing home, an earlier need for transfer from an assisted-living facility to a higher-level health care facility, and increased caregiver depression and burden.

In addition, depression is the factor most closely related to poor quality of life among patients with Parkinson’s disease. “Depression in Parkinson’s disease has been associated with a more rapid deterioration of motor and cognitive function, especially executive function, and a greater likelihood of displaying psychotic symptoms and physical disability,” said Dr. Kanner. In people with Parkinson’s disease, depression is associated with impairment in set shifting and concept formation.

Depression Complicates Epilepsy Treatment
Several studies describe the various negative effects that depression has among people with epilepsy. Investigators in the United Kingdom concluded that people with a lifetime history of depression before epilepsy onset were twice as likely to develop treatment-resistant epilepsy than people without depression before epilepsy onset.

In an Australian study of people with new-onset epilepsy, comorbid symptoms of depression and anxiety at epilepsy diagnosis were associated with a lower likelihood of being seizure-free at 52 weeks of treatment. Research by Dr. Kanner and colleagues found that among patients who became seizure-free after temporal lobectomy, 12% had had a lifetime history of depression. Approximately 80% of people who had resistant seizures after surgery had had a lifetime history of depression.

A multicenter study of people with epilepsy indicated that patients with depression or anxiety were significantly more likely to have a greater number and severity of adverse events from antiepileptic drugs. Other data indicate a high correlation between severity of depression and poor quality of life among individuals with treatment-resistant temporal lobe epilepsy. This investigation also found no correlation between seizure frequency and quality of life.

—Erik Greb

NAPLES, FLORIDA—Psychiatric comorbidities, particularly depression, worsen the course of major neurologic conditions, according to research described at the 42nd Annual Meeting of the Southern Clinical Neurological Society. Among individuals with neurologic diseases, depression is associated with greater cognitive deficits, greater impairments in activities of daily living, and lower quality of life.

“Intuitively, we would think that if we treat those comorbid depressive disorders, patients’ course would get better,” said Andres M. Kanner, MD, Professor of Clinical Neurology at the University of Miami Miller School of Medicine. “The problem is that there’s been such apathy about paying attention to comorbid depressive disorders in neurologic conditions that there are no good data on their treatment.” This lack of data needs to be addressed, he added.

A Bidirectional Relationship
The pathogenic mechanisms operant in the development of mood disorders include environmental factors (eg, stressful events), genetic predispositions, and neurotransmitter and neuroendocrine disturbances, which, in turn, can result in structural and functional changes in the CNS. These changes could explain why the course of a neurologic condition is worse among patients with depression than among patients without depression.

Various studies have suggested that depression and some neurologic disorders share common pathogenic mechanisms. For example, data indicate that decreased binding of the serotonin 1A receptor in the hippocampus, insula, amygdala, cingulate gyrus, and Raphe nuclei occurs in temporal lobe epilepsy and depression. Depression also is associated with low platelet serotonin concentration, which can yield a higher platelet adhesivity, and increased secretion of cytokines, which may be associated with vasculitic processes. These factors may heighten the risk of stroke. Likewise, glutamate, one of the neurotransmitters implicated in epileptogenesis, is present at high levels in the CSF, plasma, and cortex of patients with depression.

Depression is common among patients with neurologic disorders. Population-based studies suggest that one in every three patients who develop stroke, epilepsy, migraine, or Parkinson’s disease will develop depression. Between 27% and 54% of patients with multiple sclerosis (MS) have had an episode of major depressive disorder. And between 30% and 50% of patients with dementia have depression.

Depression and neurologic disorders appear to have a bidirectional relationship. “Not only are people with some of the major neurologic conditions more likely to develop depression, but a history of depression is associated with a higher risk of developing several of the neurologic conditions, such as epilepsy, migraine, stroke, Parkinson’s disease, and dementia,” said Dr. Kanner. This complex interaction also affects clinical treatment. A patient’s family psychiatric history, psychiatric comorbidity, and stressful life events can influence his or her response to pharmacotherapy, as well as the development of psychiatric adverse events to pharmacologic and surgical treatment.

Depression’s Effects in Neurologic Diseases
The negative effects of mood disorders vary according to the patient’s neurologic disease. Researchers at Johns Hopkins University found that patients with stroke and major poststroke depression had significantly more cognitive deficits than patients with stroke who did not have depression. In a follow-up study, the same researchers found that major poststroke depression was associated with greater cognitive impairment at two years after stroke onset. A separate investigation indicated that in-hospital poststroke depression was the most important predictor of poor recovery in activities of daily living after two years. Other data suggested that mortality risk was 50% higher for patients with stroke and poststroke depression than for patients with stroke without poststroke depression.

Among people with MS, depression significantly and independently affects quality of life. In one trial, depression was a stronger predictor of poor quality of life than disease severity, as measured by the Expanded Disability Status Scale. A study of 136 patients with MS found that depression decreased quality of life by reducing energy, mental health, sexual function, and cognitive function.

Among people with Alzheimer’s dementia, depression is a predictor of cognitive decline and is associated with greater impairment in activities of daily living. For this population, depression also is associated with an earlier need for placement in a nursing home, an earlier need for transfer from an assisted-living facility to a higher-level health care facility, and increased caregiver depression and burden.

In addition, depression is the factor most closely related to poor quality of life among patients with Parkinson’s disease. “Depression in Parkinson’s disease has been associated with a more rapid deterioration of motor and cognitive function, especially executive function, and a greater likelihood of displaying psychotic symptoms and physical disability,” said Dr. Kanner. In people with Parkinson’s disease, depression is associated with impairment in set shifting and concept formation.

Depression Complicates Epilepsy Treatment
Several studies describe the various negative effects that depression has among people with epilepsy. Investigators in the United Kingdom concluded that people with a lifetime history of depression before epilepsy onset were twice as likely to develop treatment-resistant epilepsy than people without depression before epilepsy onset.

In an Australian study of people with new-onset epilepsy, comorbid symptoms of depression and anxiety at epilepsy diagnosis were associated with a lower likelihood of being seizure-free at 52 weeks of treatment. Research by Dr. Kanner and colleagues found that among patients who became seizure-free after temporal lobectomy, 12% had had a lifetime history of depression. Approximately 80% of people who had resistant seizures after surgery had had a lifetime history of depression.

A multicenter study of people with epilepsy indicated that patients with depression or anxiety were significantly more likely to have a greater number and severity of adverse events from antiepileptic drugs. Other data indicate a high correlation between severity of depression and poor quality of life among individuals with treatment-resistant temporal lobe epilepsy. This investigation also found no correlation between seizure frequency and quality of life.

—Erik Greb

For patients with multiple sclerosis (MS), having no evidence of disease activity (NEDA) at two years has a positive predictive value of 78.3% for absence of progression at seven years, according to research published in the February issue of JAMA Neurology.

Although 46% of patients in the study had achieved NEDA at one year, 7.9% of patients maintained NEDA after seven years. These findings result from a longitudinal study of 215 patients with clinically isolated syndrome or relapsing-remitting MS.

Dalia L. Rotstein, MD, Assistant Professor of Neurology at the University of Toronto, and her colleagues analyzed data for members of the Comprehensive Longitudinal Investigation of MS at Brigham and Women’s Hospital (CLIMB) cohort who had a minimum of seven years of prospective MRI and clinical follow-up data.

The concept of NEDA is common in the treatment of diseases such as cancer and rheumatoid arthritis, but is considered a secondary outcome measure in MS. NEDA is defined as the absence of new or enlarging T2 lesions or T1 gadolinium-enhancing lesions on MRI and the absence of sustained Expanded Disability Status Scale score progression or clinical relapse.

During the study period, clinical and MRI indicators of disease progress were dissociated, said the investigators. The percentage of patients who had no evidence of disease progression on one measure but not on another ranged from 42.9% at year 2 to 30.6% at year 7. No MRI disease activity occurred in 23.5% of patients at year 1 and in 14.8% of patients at year 7, but the percentage of participants who had NEDA was about 15% at both time points.

“Although NEDA has the potential to become not only a key outcome measure of disease-modifying therapy, but also a treat-to-target goal, it will require a comprehensive approach that integrates advances in MRI technology, linkage of blood and CSF biomarkers, and a high degree of cooperation among investigators,” said the authors.

The study did not explore the effects of different treatment approaches, but NEDA is a necessary, albeit ambitious, benchmark that likely will become an important goal in MS care, said Jaime Imitola, MD, Assistant Professor of Neurology and Neuroscience, and Michael K. Racke, MD, Professor and Chair of the Department of Neurology, both at Ohio State University in Columbus, in an accompanying editorial.

Although the study suggests that NEDA is difficult to maintain over the long term, the outcome has prognostic value at two years. “Neurologists must start discussing the goal of disease-activity-free status with their patients to take NEDA from the uniform environment of clinical trials to actual clinical practice,” said Drs. Imitola and Racke.

—Bianca Nogrady

For patients with multiple sclerosis (MS), having no evidence of disease activity (NEDA) at two years has a positive predictive value of 78.3% for absence of progression at seven years, according to research published in the February issue of JAMA Neurology.

Although 46% of patients in the study had achieved NEDA at one year, 7.9% of patients maintained NEDA after seven years. These findings result from a longitudinal study of 215 patients with clinically isolated syndrome or relapsing-remitting MS.

Dalia L. Rotstein, MD, Assistant Professor of Neurology at the University of Toronto, and her colleagues analyzed data for members of the Comprehensive Longitudinal Investigation of MS at Brigham and Women’s Hospital (CLIMB) cohort who had a minimum of seven years of prospective MRI and clinical follow-up data.

The concept of NEDA is common in the treatment of diseases such as cancer and rheumatoid arthritis, but is considered a secondary outcome measure in MS. NEDA is defined as the absence of new or enlarging T2 lesions or T1 gadolinium-enhancing lesions on MRI and the absence of sustained Expanded Disability Status Scale score progression or clinical relapse.

During the study period, clinical and MRI indicators of disease progress were dissociated, said the investigators. The percentage of patients who had no evidence of disease progression on one measure but not on another ranged from 42.9% at year 2 to 30.6% at year 7. No MRI disease activity occurred in 23.5% of patients at year 1 and in 14.8% of patients at year 7, but the percentage of participants who had NEDA was about 15% at both time points.

“Although NEDA has the potential to become not only a key outcome measure of disease-modifying therapy, but also a treat-to-target goal, it will require a comprehensive approach that integrates advances in MRI technology, linkage of blood and CSF biomarkers, and a high degree of cooperation among investigators,” said the authors.

The study did not explore the effects of different treatment approaches, but NEDA is a necessary, albeit ambitious, benchmark that likely will become an important goal in MS care, said Jaime Imitola, MD, Assistant Professor of Neurology and Neuroscience, and Michael K. Racke, MD, Professor and Chair of the Department of Neurology, both at Ohio State University in Columbus, in an accompanying editorial.

Although the study suggests that NEDA is difficult to maintain over the long term, the outcome has prognostic value at two years. “Neurologists must start discussing the goal of disease-activity-free status with their patients to take NEDA from the uniform environment of clinical trials to actual clinical practice,” said Drs. Imitola and Racke.

—Bianca Nogrady

For patients with multiple sclerosis (MS), having no evidence of disease activity (NEDA) at two years has a positive predictive value of 78.3% for absence of progression at seven years, according to research published in the February issue of JAMA Neurology.

Although 46% of patients in the study had achieved NEDA at one year, 7.9% of patients maintained NEDA after seven years. These findings result from a longitudinal study of 215 patients with clinically isolated syndrome or relapsing-remitting MS.

Dalia L. Rotstein, MD, Assistant Professor of Neurology at the University of Toronto, and her colleagues analyzed data for members of the Comprehensive Longitudinal Investigation of MS at Brigham and Women’s Hospital (CLIMB) cohort who had a minimum of seven years of prospective MRI and clinical follow-up data.

The concept of NEDA is common in the treatment of diseases such as cancer and rheumatoid arthritis, but is considered a secondary outcome measure in MS. NEDA is defined as the absence of new or enlarging T2 lesions or T1 gadolinium-enhancing lesions on MRI and the absence of sustained Expanded Disability Status Scale score progression or clinical relapse.

During the study period, clinical and MRI indicators of disease progress were dissociated, said the investigators. The percentage of patients who had no evidence of disease progression on one measure but not on another ranged from 42.9% at year 2 to 30.6% at year 7. No MRI disease activity occurred in 23.5% of patients at year 1 and in 14.8% of patients at year 7, but the percentage of participants who had NEDA was about 15% at both time points.

“Although NEDA has the potential to become not only a key outcome measure of disease-modifying therapy, but also a treat-to-target goal, it will require a comprehensive approach that integrates advances in MRI technology, linkage of blood and CSF biomarkers, and a high degree of cooperation among investigators,” said the authors.

The study did not explore the effects of different treatment approaches, but NEDA is a necessary, albeit ambitious, benchmark that likely will become an important goal in MS care, said Jaime Imitola, MD, Assistant Professor of Neurology and Neuroscience, and Michael K. Racke, MD, Professor and Chair of the Department of Neurology, both at Ohio State University in Columbus, in an accompanying editorial.

Although the study suggests that NEDA is difficult to maintain over the long term, the outcome has prognostic value at two years. “Neurologists must start discussing the goal of disease-activity-free status with their patients to take NEDA from the uniform environment of clinical trials to actual clinical practice,” said Drs. Imitola and Racke.

—Bianca Nogrady

Intense immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) is significantly superior to mitoxantrone in reducing MRI activity in patients with severe multiple sclerosis (MS), according to a study published online ahead of print February 11 in Neurology.

The study involved 21 people whose MS-related disability had increased during the previous year despite treatment with first-line MS drugs. Participants’ average age was 36, and their average disability level required them to use a cane or crutch to walk.

Giovanni L. Mancardi, MD, Director of the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health at the University of Genoa, and colleagues conducted a multicenter, phase II trial. They enrolled patients with secondary progressive or relapsing-remitting MS who had a documented increase in the year prior to enrollment on the Expanded Disability Status Scale (EDSS) score and one or more gadolinium-enhancing areas.

The primary end point was the cumulative number of new T2 lesions in the four years following randomization. Secondary end points were the cumulative number of gadolinium-enhancing lesions, relapse rate, and disability progression. A total of 21 patients were randomized. Following immunosupression, 12 patients received mitoxantrone (20 mg every month for six months) and nine patients underwent AHSCT. Seventeen patients had postbaseline evaluable MRI scans.

Intense immunosuppression followed by AHSCT reduced by 79% the number of new T2 lesions, compared with mitoxantrone treatment (2.5 new T2 lesions vs eight new T2 lesions, respectively). AHSCT also reduced gadolinium-enhancing lesions. None of the people who received AHSCT had a new gadolinium-enhancing lesion during the study, while 56% of those taking mitoxantrone had at least one new lesion. Annualized relapse rate was also reduced, but no difference was seen in the progression of disability.

AHSCT “appears to reset the immune system,” said Dr. Mancardi, lead author of the study. “With these results, we can speculate that stem cell treatment may profoundly affect the course of the disease.

“More research is needed with larger numbers of patients who are randomized to receive either the stem cell transplant or an approved therapy, but it’s very exciting to see that this treatment may be so superior to a current treatment for people with severe MS that is not responding well to standard treatments,” Dr. Mancardi said.

Intense immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) is significantly superior to mitoxantrone in reducing MRI activity in patients with severe multiple sclerosis (MS), according to a study published online ahead of print February 11 in Neurology.

The study involved 21 people whose MS-related disability had increased during the previous year despite treatment with first-line MS drugs. Participants’ average age was 36, and their average disability level required them to use a cane or crutch to walk.

Giovanni L. Mancardi, MD, Director of the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health at the University of Genoa, and colleagues conducted a multicenter, phase II trial. They enrolled patients with secondary progressive or relapsing-remitting MS who had a documented increase in the year prior to enrollment on the Expanded Disability Status Scale (EDSS) score and one or more gadolinium-enhancing areas.

The primary end point was the cumulative number of new T2 lesions in the four years following randomization. Secondary end points were the cumulative number of gadolinium-enhancing lesions, relapse rate, and disability progression. A total of 21 patients were randomized. Following immunosupression, 12 patients received mitoxantrone (20 mg every month for six months) and nine patients underwent AHSCT. Seventeen patients had postbaseline evaluable MRI scans.

Intense immunosuppression followed by AHSCT reduced by 79% the number of new T2 lesions, compared with mitoxantrone treatment (2.5 new T2 lesions vs eight new T2 lesions, respectively). AHSCT also reduced gadolinium-enhancing lesions. None of the people who received AHSCT had a new gadolinium-enhancing lesion during the study, while 56% of those taking mitoxantrone had at least one new lesion. Annualized relapse rate was also reduced, but no difference was seen in the progression of disability.

AHSCT “appears to reset the immune system,” said Dr. Mancardi, lead author of the study. “With these results, we can speculate that stem cell treatment may profoundly affect the course of the disease.

“More research is needed with larger numbers of patients who are randomized to receive either the stem cell transplant or an approved therapy, but it’s very exciting to see that this treatment may be so superior to a current treatment for people with severe MS that is not responding well to standard treatments,” Dr. Mancardi said.

Intense immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) is significantly superior to mitoxantrone in reducing MRI activity in patients with severe multiple sclerosis (MS), according to a study published online ahead of print February 11 in Neurology.

The study involved 21 people whose MS-related disability had increased during the previous year despite treatment with first-line MS drugs. Participants’ average age was 36, and their average disability level required them to use a cane or crutch to walk.

Giovanni L. Mancardi, MD, Director of the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health at the University of Genoa, and colleagues conducted a multicenter, phase II trial. They enrolled patients with secondary progressive or relapsing-remitting MS who had a documented increase in the year prior to enrollment on the Expanded Disability Status Scale (EDSS) score and one or more gadolinium-enhancing areas.

The primary end point was the cumulative number of new T2 lesions in the four years following randomization. Secondary end points were the cumulative number of gadolinium-enhancing lesions, relapse rate, and disability progression. A total of 21 patients were randomized. Following immunosupression, 12 patients received mitoxantrone (20 mg every month for six months) and nine patients underwent AHSCT. Seventeen patients had postbaseline evaluable MRI scans.

Intense immunosuppression followed by AHSCT reduced by 79% the number of new T2 lesions, compared with mitoxantrone treatment (2.5 new T2 lesions vs eight new T2 lesions, respectively). AHSCT also reduced gadolinium-enhancing lesions. None of the people who received AHSCT had a new gadolinium-enhancing lesion during the study, while 56% of those taking mitoxantrone had at least one new lesion. Annualized relapse rate was also reduced, but no difference was seen in the progression of disability.

AHSCT “appears to reset the immune system,” said Dr. Mancardi, lead author of the study. “With these results, we can speculate that stem cell treatment may profoundly affect the course of the disease.

“More research is needed with larger numbers of patients who are randomized to receive either the stem cell transplant or an approved therapy, but it’s very exciting to see that this treatment may be so superior to a current treatment for people with severe MS that is not responding well to standard treatments,” Dr. Mancardi said.

CHICAGO—Approximately 60% of patients with multiple sclerosis (MS) and uveitis receive diagnoses of both diseases within a five-year period, according to a large retrospective study presented at the 118th Annual Meeting of the American Academy of Ophthalmology. Although the association between the eye condition and MS has long been known, this study is the first to provide a detailed description of the relative onset of uveitis and that of MS, as well as to calculate the likelihood of an MS diagnosis among patients with uveitis.

Uveitis can be a sign of MS, and between 1% and 10% of people with MS have uveitis. To achieve a better understanding of the association between the two diseases, researchers from Casey Eye Institute at the Oregon Health and Science University in Portland and investigators from the University of Heidelberg in Germany searched a Casey Eye Institute database of approximately 3,000 patients with uveitis and a University of Heidelberg database of 5,319 patients with uveitis who presented between 1985 and 2013. The researchers identified 24 patients from the Casey Eye Institute and 89 patients from the University of Heidelberg who fulfilled the diagnostic criteria for uveitis and MS. Thus, 113 individuals were included in the study.

Compared with the prevalence of MS in American and European populations, MS is 18 times and 21 times more common in American and European populations with uveitis, respectively, according to the researchers. They found that MS was diagnosed before uveitis in 28 (29%) patients, simultaneously in 15 (15%) patients, and after uveitis diagnosis in 54 (56%) patients.

“With a population size four times larger than [that of] any study to date on this topic, our study provides a wealth of clinical information to allow clinicians to make more accurate diagnoses, while giving patients a better understanding of their prognosis,” said Wyatt Messenger, MD, a research fellow at the University of Utah in Salt Lake City and former lead researcher from the Casey Eye Institute. “Knowing more about the onset may enable patients to seek treatment earlier, therefore slowing the progression of the disease and limiting the damage done to the nervous system.”

In addition, this study is the first to estimate the relative frequency of anatomical subtypes of uveitis in patients with MS. Traditionally, patients with MS are thought to present most often with intermediate uveitis, which also is referred to as pars planitis. Although 80% of cases in this study had intermediate uveitis at the time of MS diagnosis, the researchers found that nearly one in six participants presented with anterior uveitis. The investigators also observed that visual acuity is generally stable in this population; the majority of patients improved during follow-up.

A major limitation of the study is the lack of availability of brain MRI for all of the patients, according to the researchers. The study also lacks detailed neurologic studies, which would have allowed investigators to correlate the patients’ uveitis with their neurologic disease.

CHICAGO—Approximately 60% of patients with multiple sclerosis (MS) and uveitis receive diagnoses of both diseases within a five-year period, according to a large retrospective study presented at the 118th Annual Meeting of the American Academy of Ophthalmology. Although the association between the eye condition and MS has long been known, this study is the first to provide a detailed description of the relative onset of uveitis and that of MS, as well as to calculate the likelihood of an MS diagnosis among patients with uveitis.

Uveitis can be a sign of MS, and between 1% and 10% of people with MS have uveitis. To achieve a better understanding of the association between the two diseases, researchers from Casey Eye Institute at the Oregon Health and Science University in Portland and investigators from the University of Heidelberg in Germany searched a Casey Eye Institute database of approximately 3,000 patients with uveitis and a University of Heidelberg database of 5,319 patients with uveitis who presented between 1985 and 2013. The researchers identified 24 patients from the Casey Eye Institute and 89 patients from the University of Heidelberg who fulfilled the diagnostic criteria for uveitis and MS. Thus, 113 individuals were included in the study.

Compared with the prevalence of MS in American and European populations, MS is 18 times and 21 times more common in American and European populations with uveitis, respectively, according to the researchers. They found that MS was diagnosed before uveitis in 28 (29%) patients, simultaneously in 15 (15%) patients, and after uveitis diagnosis in 54 (56%) patients.

“With a population size four times larger than [that of] any study to date on this topic, our study provides a wealth of clinical information to allow clinicians to make more accurate diagnoses, while giving patients a better understanding of their prognosis,” said Wyatt Messenger, MD, a research fellow at the University of Utah in Salt Lake City and former lead researcher from the Casey Eye Institute. “Knowing more about the onset may enable patients to seek treatment earlier, therefore slowing the progression of the disease and limiting the damage done to the nervous system.”

In addition, this study is the first to estimate the relative frequency of anatomical subtypes of uveitis in patients with MS. Traditionally, patients with MS are thought to present most often with intermediate uveitis, which also is referred to as pars planitis. Although 80% of cases in this study had intermediate uveitis at the time of MS diagnosis, the researchers found that nearly one in six participants presented with anterior uveitis. The investigators also observed that visual acuity is generally stable in this population; the majority of patients improved during follow-up.

A major limitation of the study is the lack of availability of brain MRI for all of the patients, according to the researchers. The study also lacks detailed neurologic studies, which would have allowed investigators to correlate the patients’ uveitis with their neurologic disease.

CHICAGO—Approximately 60% of patients with multiple sclerosis (MS) and uveitis receive diagnoses of both diseases within a five-year period, according to a large retrospective study presented at the 118th Annual Meeting of the American Academy of Ophthalmology. Although the association between the eye condition and MS has long been known, this study is the first to provide a detailed description of the relative onset of uveitis and that of MS, as well as to calculate the likelihood of an MS diagnosis among patients with uveitis.

Uveitis can be a sign of MS, and between 1% and 10% of people with MS have uveitis. To achieve a better understanding of the association between the two diseases, researchers from Casey Eye Institute at the Oregon Health and Science University in Portland and investigators from the University of Heidelberg in Germany searched a Casey Eye Institute database of approximately 3,000 patients with uveitis and a University of Heidelberg database of 5,319 patients with uveitis who presented between 1985 and 2013. The researchers identified 24 patients from the Casey Eye Institute and 89 patients from the University of Heidelberg who fulfilled the diagnostic criteria for uveitis and MS. Thus, 113 individuals were included in the study.

Compared with the prevalence of MS in American and European populations, MS is 18 times and 21 times more common in American and European populations with uveitis, respectively, according to the researchers. They found that MS was diagnosed before uveitis in 28 (29%) patients, simultaneously in 15 (15%) patients, and after uveitis diagnosis in 54 (56%) patients.

“With a population size four times larger than [that of] any study to date on this topic, our study provides a wealth of clinical information to allow clinicians to make more accurate diagnoses, while giving patients a better understanding of their prognosis,” said Wyatt Messenger, MD, a research fellow at the University of Utah in Salt Lake City and former lead researcher from the Casey Eye Institute. “Knowing more about the onset may enable patients to seek treatment earlier, therefore slowing the progression of the disease and limiting the damage done to the nervous system.”

In addition, this study is the first to estimate the relative frequency of anatomical subtypes of uveitis in patients with MS. Traditionally, patients with MS are thought to present most often with intermediate uveitis, which also is referred to as pars planitis. Although 80% of cases in this study had intermediate uveitis at the time of MS diagnosis, the researchers found that nearly one in six participants presented with anterior uveitis. The investigators also observed that visual acuity is generally stable in this population; the majority of patients improved during follow-up.

A major limitation of the study is the lack of availability of brain MRI for all of the patients, according to the researchers. The study also lacks detailed neurologic studies, which would have allowed investigators to correlate the patients’ uveitis with their neurologic disease.

BOSTON—The concentration of GABA in the sensorimotor cortex and in the hippocampus is decreased significantly in patients with secondary progressive multiple sclerosis (MS), compared with healthy individuals, according to research described at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The decreased concentration in the sensorimotor cortex is associated with impaired motor performance.

The reduced GABA levels likely reflect pathologic changes that result from neuronal loss and may indicate a decrease in synaptic density, said Niamh Cawley, MRCPI, Clinical Research Associate at University College London.

Clinical and Cognitive Assessments
For their investigation, Dr. Cawley and colleagues enrolled patients with secondary progressive MS and an Expanded Disability Status Scale (EDSS) score of between 4 and 6.5. Patients taking medications that alter the GABAnergic system were excluded from the study. The researchers recruited healthy controls as a comparison group.

The investigators performed cognitive assessments that examined attention and information processing speed, executive function, working memory, and visual and verbal memory. Clinical assessments included EDSS, the Nine-Hole Peg Test, the Timed Walk Test, grip strength of the right upper limb, muscle strength of the right upper and lower limbs, and vibration sensation of the right upper and lower limbs. Brain images were obtained with a 3-T scanner.

The researchers used a general linear model to compare differences in metabolite concentration between patients and controls, while adjusting for age, gender, and gray matter fraction within the spectroscopic voxel. A linear regression model enabled Dr. Cawley’s group to examine the relationships between cognitive and clinical scores and GABA concentrations. Data were adjusted for age, gender, gray matter fraction, and gray matter lesions within the spectroscopic voxel.

GABA Was Decreased in Two Brain Regions
Data were analyzed for 30 patients and 17 controls. Patients’ median EDSS score was 6. Patients performed significantly worse than controls on grip strength, muscle strength, the Nine-Hole Peg Test, and vibration sensation. Patients also performed significantly worse on digit span and immediate and delayed verbal recall.

The investigators found a significant decrease in the concentration of GABA in the sensorimotor cortex and in the hippocampus in patients, compared with controls. They did not observe a significant difference in the concentration of GABA in the prefrontal cortex. Data analysis revealed a significant positive correlation between the concentration of GABA in the sensorimotor cortex and scores on the Nine-Hole Peg Test, as well as grip strength and muscle strength. No significant correlation was seen between the concentration of GABA in the prefrontal cortex or the hippocampus and any cognitive assessments.

Although the current results are consistent with a previous post mortem investigation that demonstrated reduced presynaptic and postsynaptic GABA neurotransmission in patients with progressive MS, the findings diverge from those of Bhattacharyya et al, who found an inverse correlation between scores obtained on the Nine-Hole Peg Test and concentration of GABA in the sensorimotor cortex among patients with relapsing-remitting MS. “Our findings in patients with progressive disease are likely to reflect the loss of the compensatory mechanisms associated with plasticity due to this neuronal loss,” said Dr. Cawley. She plans to follow the patients over time to monitor GABA changes in the three brain regions, as well as to examine the association between GABA levels and functional changes.

—Erik Greb

BOSTON—The concentration of GABA in the sensorimotor cortex and in the hippocampus is decreased significantly in patients with secondary progressive multiple sclerosis (MS), compared with healthy individuals, according to research described at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The decreased concentration in the sensorimotor cortex is associated with impaired motor performance.

The reduced GABA levels likely reflect pathologic changes that result from neuronal loss and may indicate a decrease in synaptic density, said Niamh Cawley, MRCPI, Clinical Research Associate at University College London.

Clinical and Cognitive Assessments
For their investigation, Dr. Cawley and colleagues enrolled patients with secondary progressive MS and an Expanded Disability Status Scale (EDSS) score of between 4 and 6.5. Patients taking medications that alter the GABAnergic system were excluded from the study. The researchers recruited healthy controls as a comparison group.

The investigators performed cognitive assessments that examined attention and information processing speed, executive function, working memory, and visual and verbal memory. Clinical assessments included EDSS, the Nine-Hole Peg Test, the Timed Walk Test, grip strength of the right upper limb, muscle strength of the right upper and lower limbs, and vibration sensation of the right upper and lower limbs. Brain images were obtained with a 3-T scanner.

The researchers used a general linear model to compare differences in metabolite concentration between patients and controls, while adjusting for age, gender, and gray matter fraction within the spectroscopic voxel. A linear regression model enabled Dr. Cawley’s group to examine the relationships between cognitive and clinical scores and GABA concentrations. Data were adjusted for age, gender, gray matter fraction, and gray matter lesions within the spectroscopic voxel.

GABA Was Decreased in Two Brain Regions
Data were analyzed for 30 patients and 17 controls. Patients’ median EDSS score was 6. Patients performed significantly worse than controls on grip strength, muscle strength, the Nine-Hole Peg Test, and vibration sensation. Patients also performed significantly worse on digit span and immediate and delayed verbal recall.

The investigators found a significant decrease in the concentration of GABA in the sensorimotor cortex and in the hippocampus in patients, compared with controls. They did not observe a significant difference in the concentration of GABA in the prefrontal cortex. Data analysis revealed a significant positive correlation between the concentration of GABA in the sensorimotor cortex and scores on the Nine-Hole Peg Test, as well as grip strength and muscle strength. No significant correlation was seen between the concentration of GABA in the prefrontal cortex or the hippocampus and any cognitive assessments.

Although the current results are consistent with a previous post mortem investigation that demonstrated reduced presynaptic and postsynaptic GABA neurotransmission in patients with progressive MS, the findings diverge from those of Bhattacharyya et al, who found an inverse correlation between scores obtained on the Nine-Hole Peg Test and concentration of GABA in the sensorimotor cortex among patients with relapsing-remitting MS. “Our findings in patients with progressive disease are likely to reflect the loss of the compensatory mechanisms associated with plasticity due to this neuronal loss,” said Dr. Cawley. She plans to follow the patients over time to monitor GABA changes in the three brain regions, as well as to examine the association between GABA levels and functional changes.

—Erik Greb

BOSTON—The concentration of GABA in the sensorimotor cortex and in the hippocampus is decreased significantly in patients with secondary progressive multiple sclerosis (MS), compared with healthy individuals, according to research described at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The decreased concentration in the sensorimotor cortex is associated with impaired motor performance.

The reduced GABA levels likely reflect pathologic changes that result from neuronal loss and may indicate a decrease in synaptic density, said Niamh Cawley, MRCPI, Clinical Research Associate at University College London.

Clinical and Cognitive Assessments
For their investigation, Dr. Cawley and colleagues enrolled patients with secondary progressive MS and an Expanded Disability Status Scale (EDSS) score of between 4 and 6.5. Patients taking medications that alter the GABAnergic system were excluded from the study. The researchers recruited healthy controls as a comparison group.

The investigators performed cognitive assessments that examined attention and information processing speed, executive function, working memory, and visual and verbal memory. Clinical assessments included EDSS, the Nine-Hole Peg Test, the Timed Walk Test, grip strength of the right upper limb, muscle strength of the right upper and lower limbs, and vibration sensation of the right upper and lower limbs. Brain images were obtained with a 3-T scanner.

The researchers used a general linear model to compare differences in metabolite concentration between patients and controls, while adjusting for age, gender, and gray matter fraction within the spectroscopic voxel. A linear regression model enabled Dr. Cawley’s group to examine the relationships between cognitive and clinical scores and GABA concentrations. Data were adjusted for age, gender, gray matter fraction, and gray matter lesions within the spectroscopic voxel.

GABA Was Decreased in Two Brain Regions
Data were analyzed for 30 patients and 17 controls. Patients’ median EDSS score was 6. Patients performed significantly worse than controls on grip strength, muscle strength, the Nine-Hole Peg Test, and vibration sensation. Patients also performed significantly worse on digit span and immediate and delayed verbal recall.

The investigators found a significant decrease in the concentration of GABA in the sensorimotor cortex and in the hippocampus in patients, compared with controls. They did not observe a significant difference in the concentration of GABA in the prefrontal cortex. Data analysis revealed a significant positive correlation between the concentration of GABA in the sensorimotor cortex and scores on the Nine-Hole Peg Test, as well as grip strength and muscle strength. No significant correlation was seen between the concentration of GABA in the prefrontal cortex or the hippocampus and any cognitive assessments.

Although the current results are consistent with a previous post mortem investigation that demonstrated reduced presynaptic and postsynaptic GABA neurotransmission in patients with progressive MS, the findings diverge from those of Bhattacharyya et al, who found an inverse correlation between scores obtained on the Nine-Hole Peg Test and concentration of GABA in the sensorimotor cortex among patients with relapsing-remitting MS. “Our findings in patients with progressive disease are likely to reflect the loss of the compensatory mechanisms associated with plasticity due to this neuronal loss,” said Dr. Cawley. She plans to follow the patients over time to monitor GABA changes in the three brain regions, as well as to examine the association between GABA levels and functional changes.

—Erik Greb

BOSTON—Neuropsychiatric disorders, particularly depression and anxiety, are more common among people with multiple sclerosis (MS) than among the general population, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

Many of these disorders are treatable, and patients may respond well to medication.

“When you’ve got a disease without cure affecting young and middle-aged people, good symptom management becomes important,” said Anthony Feinstein, MBBCh, PhD, Associate Scientist at Sunnybrook Health Sciences Center in Toronto. Available therapies for neuropsychiatric disorders often can improve quality of life for patients with MS, “so the diagnosis should not be missed,” he added.

Major Depression
One in two patients with MS will develop major depression during his or her lifetime. Changes in appetite, insomnia, fatigue, and diminished ability to concentrate are hallmarks of depression, but MS also may cause these symptoms. Self-report questionnaires such as the Beck Depression Inventory and the Hospital Anxiety and Depression Scale can help neurologists determine whether a patient’s symptoms result from depression. The dexamethasone suppression test also may help confirm a diagnosis of depression. If a patient’s cortisol level remains high after a single dose of dexamethasone, then he or she may have depression.

For patients with MS and depression, a neurologist may first prescribe monotherapy with a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine. If treatment fails, the neurologist may switch to another SSRI or a serotonin–norepinephrine reuptake inhibitor such as venlafaxine or mirtazapine. These agents sometimes cause sexual difficulties, but bupropion or mirtazepine can treat depression effectively without causing this side effect, said Dr. Feinstein. If the patient does not respond to monotherapy, combination therapy may be appropriate. Combination therapy could include an antidepressant plus methylphenidate or lithium carbonate.

If combination therapy is not effective and the patient is severely depressed and suicidal, electroconvulsive therapy (ECT) may be an option. The guidelines for this therapy are strict, and it is “a safe treatment for patients with MS,” said Dr. Feinstein. ECT carries a small risk of MS relapse, so a neurologist should determine whether the patient has active disease. “We give our patients a gadolinium-enhanced MRI before we consider ECT,” said Dr. Feinstein. “If there’s no contrast enhancement and no active disease, we think that ECT is quite safe, and the response rate is excellent.”

Patients who do not want to take medication may benefit from cognitive behavioral therapy (CBT). Evidence suggests that CBT, which Cochrane Review endorses, is as effective for depression as SSRIs. CBT can be administered to individuals, to groups, or by telephone. A variant of CBT called mindfulness-based therapy also has been effective in patients with MS and depression. The advantage of CBT is its lack of side effects, but not every neurologist has access to a cognitive behavioral therapist, said Dr. Feinstein.

Interest in exercise as a treatment for depression has been rising, but no study of exercise has yet had depression relief as its primary end point. Studies in which depression relief was a secondary end point suggest that exercise is beneficial, but until there’s a randomized controlled study of exercise with depression relief as a primary end point, “the jury’s going to be out on this,” said Dr. Feinstein.

Anxiety
Anxiety is more common than depression in patients with MS, and the two disorders often are comorbid. Like depression, anxiety has symptoms that may be ascribed mistakenly to MS. The Hospital Anxiety Depression Scale can help neurologists determine whether a patient with MS has anxiety.

Few researchers have studied the treatment of anxiety in patients with MS, and none have examined pharmacologic therapies. Current data do suggest that CBT is effective, however. Stress inoculation therapy, a form of CBT, is intended to reduce negative thoughts and minimize stress. This therapy “is potentially effective in reducing anxiety,” said Dr. Feinstein. Randomized controlled trials indicate that CBT helps to reduce the anxiety that results from a diagnosis of MS. Needle phobia, which affects compliance with treatment, also can respond well to CBT.

Pseudobulbar Affect and Other Disorders
Approximately 10% of patients with MS have pseudobulbar affect, which responds well to medication. Low-dose amitriptyline, SSRIs, levodopa, and amantadine treat this condition effectively. In addition, the FDA recently approved dextromethorphan–quinidine for the treatment of pseudobulbar affect, and a 2006 study published in Annals of Neurology showed that the combination was effective for patients with pseudobulbar affect and MS. “When you treat this particular syndrome, you’re going to get a response in about 48 to 72 hours,” said Dr. Feinstein. “If you treat someone with major depression with medication, the response time is usually about two weeks.”

Bipolar affective disorder is twice as common among individuals with MS as it is in the general population. The disorder is characterized by grandiosity, elevated mood, irritability, and increased motor activity. No data are available about treating bipolar affective disorder in patients with MS, so neurologists must consult the psychiatric literature. “Patients respond well to mood-stabilizing medication such as lithium or valproic acid,” said Dr. Feinstein. “If your patients are psychotic, occasionally you have to introduce an antipsychotic agent as well.”

Between 9% and 13% of patients with MS have euphoria, an exaggerated feeling of mental and physical well-being. People with MS and euphoria tend to have significant brain atrophy and heavy lesion load, and no treatments for euphoria exist. Treating the disorder might be undesirable anyway, although it adds to the burden on the patient’s caregiver, said Dr. Feinstein.

—Erik Greb

BOSTON—Neuropsychiatric disorders, particularly depression and anxiety, are more common among people with multiple sclerosis (MS) than among the general population, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

Many of these disorders are treatable, and patients may respond well to medication.

“When you’ve got a disease without cure affecting young and middle-aged people, good symptom management becomes important,” said Anthony Feinstein, MBBCh, PhD, Associate Scientist at Sunnybrook Health Sciences Center in Toronto. Available therapies for neuropsychiatric disorders often can improve quality of life for patients with MS, “so the diagnosis should not be missed,” he added.

Major Depression
One in two patients with MS will develop major depression during his or her lifetime. Changes in appetite, insomnia, fatigue, and diminished ability to concentrate are hallmarks of depression, but MS also may cause these symptoms. Self-report questionnaires such as the Beck Depression Inventory and the Hospital Anxiety and Depression Scale can help neurologists determine whether a patient’s symptoms result from depression. The dexamethasone suppression test also may help confirm a diagnosis of depression. If a patient’s cortisol level remains high after a single dose of dexamethasone, then he or she may have depression.

For patients with MS and depression, a neurologist may first prescribe monotherapy with a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine. If treatment fails, the neurologist may switch to another SSRI or a serotonin–norepinephrine reuptake inhibitor such as venlafaxine or mirtazapine. These agents sometimes cause sexual difficulties, but bupropion or mirtazepine can treat depression effectively without causing this side effect, said Dr. Feinstein. If the patient does not respond to monotherapy, combination therapy may be appropriate. Combination therapy could include an antidepressant plus methylphenidate or lithium carbonate.

If combination therapy is not effective and the patient is severely depressed and suicidal, electroconvulsive therapy (ECT) may be an option. The guidelines for this therapy are strict, and it is “a safe treatment for patients with MS,” said Dr. Feinstein. ECT carries a small risk of MS relapse, so a neurologist should determine whether the patient has active disease. “We give our patients a gadolinium-enhanced MRI before we consider ECT,” said Dr. Feinstein. “If there’s no contrast enhancement and no active disease, we think that ECT is quite safe, and the response rate is excellent.”

Patients who do not want to take medication may benefit from cognitive behavioral therapy (CBT). Evidence suggests that CBT, which Cochrane Review endorses, is as effective for depression as SSRIs. CBT can be administered to individuals, to groups, or by telephone. A variant of CBT called mindfulness-based therapy also has been effective in patients with MS and depression. The advantage of CBT is its lack of side effects, but not every neurologist has access to a cognitive behavioral therapist, said Dr. Feinstein.

Interest in exercise as a treatment for depression has been rising, but no study of exercise has yet had depression relief as its primary end point. Studies in which depression relief was a secondary end point suggest that exercise is beneficial, but until there’s a randomized controlled study of exercise with depression relief as a primary end point, “the jury’s going to be out on this,” said Dr. Feinstein.

Anxiety
Anxiety is more common than depression in patients with MS, and the two disorders often are comorbid. Like depression, anxiety has symptoms that may be ascribed mistakenly to MS. The Hospital Anxiety Depression Scale can help neurologists determine whether a patient with MS has anxiety.

Few researchers have studied the treatment of anxiety in patients with MS, and none have examined pharmacologic therapies. Current data do suggest that CBT is effective, however. Stress inoculation therapy, a form of CBT, is intended to reduce negative thoughts and minimize stress. This therapy “is potentially effective in reducing anxiety,” said Dr. Feinstein. Randomized controlled trials indicate that CBT helps to reduce the anxiety that results from a diagnosis of MS. Needle phobia, which affects compliance with treatment, also can respond well to CBT.

Pseudobulbar Affect and Other Disorders
Approximately 10% of patients with MS have pseudobulbar affect, which responds well to medication. Low-dose amitriptyline, SSRIs, levodopa, and amantadine treat this condition effectively. In addition, the FDA recently approved dextromethorphan–quinidine for the treatment of pseudobulbar affect, and a 2006 study published in Annals of Neurology showed that the combination was effective for patients with pseudobulbar affect and MS. “When you treat this particular syndrome, you’re going to get a response in about 48 to 72 hours,” said Dr. Feinstein. “If you treat someone with major depression with medication, the response time is usually about two weeks.”

Bipolar affective disorder is twice as common among individuals with MS as it is in the general population. The disorder is characterized by grandiosity, elevated mood, irritability, and increased motor activity. No data are available about treating bipolar affective disorder in patients with MS, so neurologists must consult the psychiatric literature. “Patients respond well to mood-stabilizing medication such as lithium or valproic acid,” said Dr. Feinstein. “If your patients are psychotic, occasionally you have to introduce an antipsychotic agent as well.”

Between 9% and 13% of patients with MS have euphoria, an exaggerated feeling of mental and physical well-being. People with MS and euphoria tend to have significant brain atrophy and heavy lesion load, and no treatments for euphoria exist. Treating the disorder might be undesirable anyway, although it adds to the burden on the patient’s caregiver, said Dr. Feinstein.

—Erik Greb

BOSTON—Neuropsychiatric disorders, particularly depression and anxiety, are more common among people with multiple sclerosis (MS) than among the general population, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

Many of these disorders are treatable, and patients may respond well to medication.

“When you’ve got a disease without cure affecting young and middle-aged people, good symptom management becomes important,” said Anthony Feinstein, MBBCh, PhD, Associate Scientist at Sunnybrook Health Sciences Center in Toronto. Available therapies for neuropsychiatric disorders often can improve quality of life for patients with MS, “so the diagnosis should not be missed,” he added.

Major Depression
One in two patients with MS will develop major depression during his or her lifetime. Changes in appetite, insomnia, fatigue, and diminished ability to concentrate are hallmarks of depression, but MS also may cause these symptoms. Self-report questionnaires such as the Beck Depression Inventory and the Hospital Anxiety and Depression Scale can help neurologists determine whether a patient’s symptoms result from depression. The dexamethasone suppression test also may help confirm a diagnosis of depression. If a patient’s cortisol level remains high after a single dose of dexamethasone, then he or she may have depression.

For patients with MS and depression, a neurologist may first prescribe monotherapy with a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine. If treatment fails, the neurologist may switch to another SSRI or a serotonin–norepinephrine reuptake inhibitor such as venlafaxine or mirtazapine. These agents sometimes cause sexual difficulties, but bupropion or mirtazepine can treat depression effectively without causing this side effect, said Dr. Feinstein. If the patient does not respond to monotherapy, combination therapy may be appropriate. Combination therapy could include an antidepressant plus methylphenidate or lithium carbonate.

If combination therapy is not effective and the patient is severely depressed and suicidal, electroconvulsive therapy (ECT) may be an option. The guidelines for this therapy are strict, and it is “a safe treatment for patients with MS,” said Dr. Feinstein. ECT carries a small risk of MS relapse, so a neurologist should determine whether the patient has active disease. “We give our patients a gadolinium-enhanced MRI before we consider ECT,” said Dr. Feinstein. “If there’s no contrast enhancement and no active disease, we think that ECT is quite safe, and the response rate is excellent.”

Patients who do not want to take medication may benefit from cognitive behavioral therapy (CBT). Evidence suggests that CBT, which Cochrane Review endorses, is as effective for depression as SSRIs. CBT can be administered to individuals, to groups, or by telephone. A variant of CBT called mindfulness-based therapy also has been effective in patients with MS and depression. The advantage of CBT is its lack of side effects, but not every neurologist has access to a cognitive behavioral therapist, said Dr. Feinstein.

Interest in exercise as a treatment for depression has been rising, but no study of exercise has yet had depression relief as its primary end point. Studies in which depression relief was a secondary end point suggest that exercise is beneficial, but until there’s a randomized controlled study of exercise with depression relief as a primary end point, “the jury’s going to be out on this,” said Dr. Feinstein.

Anxiety
Anxiety is more common than depression in patients with MS, and the two disorders often are comorbid. Like depression, anxiety has symptoms that may be ascribed mistakenly to MS. The Hospital Anxiety Depression Scale can help neurologists determine whether a patient with MS has anxiety.

Few researchers have studied the treatment of anxiety in patients with MS, and none have examined pharmacologic therapies. Current data do suggest that CBT is effective, however. Stress inoculation therapy, a form of CBT, is intended to reduce negative thoughts and minimize stress. This therapy “is potentially effective in reducing anxiety,” said Dr. Feinstein. Randomized controlled trials indicate that CBT helps to reduce the anxiety that results from a diagnosis of MS. Needle phobia, which affects compliance with treatment, also can respond well to CBT.

Pseudobulbar Affect and Other Disorders
Approximately 10% of patients with MS have pseudobulbar affect, which responds well to medication. Low-dose amitriptyline, SSRIs, levodopa, and amantadine treat this condition effectively. In addition, the FDA recently approved dextromethorphan–quinidine for the treatment of pseudobulbar affect, and a 2006 study published in Annals of Neurology showed that the combination was effective for patients with pseudobulbar affect and MS. “When you treat this particular syndrome, you’re going to get a response in about 48 to 72 hours,” said Dr. Feinstein. “If you treat someone with major depression with medication, the response time is usually about two weeks.”

Bipolar affective disorder is twice as common among individuals with MS as it is in the general population. The disorder is characterized by grandiosity, elevated mood, irritability, and increased motor activity. No data are available about treating bipolar affective disorder in patients with MS, so neurologists must consult the psychiatric literature. “Patients respond well to mood-stabilizing medication such as lithium or valproic acid,” said Dr. Feinstein. “If your patients are psychotic, occasionally you have to introduce an antipsychotic agent as well.”

Between 9% and 13% of patients with MS have euphoria, an exaggerated feeling of mental and physical well-being. People with MS and euphoria tend to have significant brain atrophy and heavy lesion load, and no treatments for euphoria exist. Treating the disorder might be undesirable anyway, although it adds to the burden on the patient’s caregiver, said Dr. Feinstein.

—Erik Greb

BOSTON—The emergence of many new disease-modifying therapies in the past 10 years has made it more challenging to choose a drug for a patient with multiple sclerosis (MS), according to an overview provided at the 2014 Joint ACTRIMS–ECTRIMS Meeting. In the United States, 12 FDA-approved therapies, including oral medications, are available for the long-term treatment of MS. These medications’ efficacy, tolerability, and safety differ widely, and patient-specific risk factors can be an important guide for choosing the appropriate treatment, said Robert Fox, MD, Vice Chair for Research at the Cleveland Clinic.

Head-to-head comparisons indicate great similarity among injectable MS therapies, which generally reduce annualized relapse rate by about 30%. The choice of an injectable therapy should be influenced by the expected side effect profile, the patient’s risk factors, patient preference about the frequency of administration, and the clinician’s comfort with the drug, said Dr. Fox. Risk stratification and mitigation should continue over time because risk factors can change, thus altering an individual’s risk for a complication.

Interferon and Glatiramer Acetate Interferon and glatiramer acetate are considered relatively safe medications, but they still require risk evaluation and mitigation, Dr. Fox said. Nonsteroidal anti-inflammatory agents and hydration can mitigate interferon’s flu-like side effects, and monitoring can reduce the drug’s associated risks of increased liver enzymes and leukopenia. Screening patients for headache, pain syndromes, and depression is also warranted before and during interferon treatment.

Glatiramer acetate entails risks of erythema, lipoatrophy, induration, and immediate post injection systemic reaction. Education and proper injection technique can mitigate the risk of skin reactions, and “education is of high importance for the post injection systemic reaction and can help avoid needless trips to the emergency room,” said Dr. Fox.

Natalizumab
Researchers have identified three main factors that can stratify the risk for progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab: John Cunningham virus (JCV) infection, prior immunosuppressant use, and duration of natalizumab treatment. Patient counseling and decision making depend greatly on which risk factors the patient has, said Dr. Fox.

Natalizumab is considered relatively safe for patients who are JCV negative, but seroconversion may occur over time. Neurologists can consider other therapies for individuals who are JCV positive, but if good alternatives are not available, the clinician may consider limiting natalizumab treatment to one to two years. Natalizumab should be avoided for patients with prior immunosuppressant use if reasonable alternatives are available. Neurologists should be vigilant for symptoms suggestive of PML and could consider performing an MRI at least every six months in JCV seropositive patients.

Antinatalizumab antibodies, which can develop particularly with prior natalizumab use, and history of anaphylaxis increase the risk of allergic reactions to natalizumab, Dr. Fox noted. Liver enzyme screening at baseline and close monitoring for patients with a history of liver disease can mitigate the risk of elevated liver enzymes.

Fingolimod
Fingolimod, particularly the first dose of the drug, entails a risk of cardiac events, and concomitant medications can increase this risk. Obtaining a cardiac history is advisable before patients start fingolimod. In addition, neurologists should perform baseline EKG, first-dose observation, and a post first-dose EKG for the patient. A standard observation lasts for six hours and includes frequent monitoring of vital signs. A 24-hour observation is indicated in patients with certain risk factors.

Fingolimod also carries a risk of macular edema that may be higher in older people or those with a history of diabetes or uveitis. Neurologists therefore should perform optical coherence tomography at baseline and at three months, said Dr. Fox. Patients with visual symptoms should be evaluated promptly for possible macular edema.

Because the drug is associated with a risk of herpes virus infections, patients should be screened for varicella zoster serology, even if they have a history of chicken pox. Seronegative patients require vaccination before starting fingolimod. Other risks include lymphopenia and leukopenia, and neurologists can monitor for these outcomes through intermittent complete blood count testing. Repeated liver function panels may mitigate the risk of increased liver enzymes, and headaches and back pain can be treated symptomatically.

Teriflunomide
Teratogenesis may be the biggest concern for patients treated with teriflunomide, which is labeled as pregnancy category X. Alternative therapies could be considered for people of childbearing potential, said Dr. Fox. Patients who receive teriflunomide should use contraception. Certain treatments can accelerate washout if a patient wants to become pregnant or inadvertently becomes pregnant while taking teriflunomide.

Teriflunomide may increase liver enzymes, therefore monitoring is appropriate. The drug is relatively contraindicated for patients with previous liver injury secondary to medications, liver disease, or tuberculosis, added Dr. Fox.

Dimethyl Fumarate
Flushing occurs in one-third of patients taking dimethyl fumarate. This side effect is benign and typically passes in 20 minutes. Taking aspirin daily can prevent flushing or reduce its severity.

One-third of patients may experience gastrointestinal side effects, including nausea, vomiting, diarrhea, and abdominal pain. The symptoms typically improve after one month. Administering the drug with food, titrating the dose slowly, and providing symptomatic treatments may help.

Dimethyl fumarate also is associated with lymphopenia, which typically takes around 12 months to develop. It is reasonable to monitor patients for lymphopenia, particularly at 12 months, and for infections, said Dr. Fox.

The drug also may be associated with a risk of PML. Four cases of PML have been reported from a total experience of approximately 170,000 patient years. Patients with PML had been receiving a formulation of dimethyl fumarate used to treat psoriasis, and some had prior immunosuppressant use and prolonged lymphopenia. After the ECTRIMS meeting, the manufacturer reported a case of PML in a patient with MS receiving dimethyl fumarate who had low lymphocyte counts for 3.5 years. Compared with natalizumab, dimethyl fumarate is associated with a lower risk of PML. “Nonetheless, it’s something that we’re keeping in the back of our mind and watching for,” said Dr. Fox. Monitoring for severely reduced lymphocyte counts may mitigate the risk of PML, he concluded.

—Erik Greb

BOSTON—The emergence of many new disease-modifying therapies in the past 10 years has made it more challenging to choose a drug for a patient with multiple sclerosis (MS), according to an overview provided at the 2014 Joint ACTRIMS–ECTRIMS Meeting. In the United States, 12 FDA-approved therapies, including oral medications, are available for the long-term treatment of MS. These medications’ efficacy, tolerability, and safety differ widely, and patient-specific risk factors can be an important guide for choosing the appropriate treatment, said Robert Fox, MD, Vice Chair for Research at the Cleveland Clinic.

Head-to-head comparisons indicate great similarity among injectable MS therapies, which generally reduce annualized relapse rate by about 30%. The choice of an injectable therapy should be influenced by the expected side effect profile, the patient’s risk factors, patient preference about the frequency of administration, and the clinician’s comfort with the drug, said Dr. Fox. Risk stratification and mitigation should continue over time because risk factors can change, thus altering an individual’s risk for a complication.

Interferon and Glatiramer Acetate Interferon and glatiramer acetate are considered relatively safe medications, but they still require risk evaluation and mitigation, Dr. Fox said. Nonsteroidal anti-inflammatory agents and hydration can mitigate interferon’s flu-like side effects, and monitoring can reduce the drug’s associated risks of increased liver enzymes and leukopenia. Screening patients for headache, pain syndromes, and depression is also warranted before and during interferon treatment.

Glatiramer acetate entails risks of erythema, lipoatrophy, induration, and immediate post injection systemic reaction. Education and proper injection technique can mitigate the risk of skin reactions, and “education is of high importance for the post injection systemic reaction and can help avoid needless trips to the emergency room,” said Dr. Fox.

Natalizumab
Researchers have identified three main factors that can stratify the risk for progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab: John Cunningham virus (JCV) infection, prior immunosuppressant use, and duration of natalizumab treatment. Patient counseling and decision making depend greatly on which risk factors the patient has, said Dr. Fox.

Natalizumab is considered relatively safe for patients who are JCV negative, but seroconversion may occur over time. Neurologists can consider other therapies for individuals who are JCV positive, but if good alternatives are not available, the clinician may consider limiting natalizumab treatment to one to two years. Natalizumab should be avoided for patients with prior immunosuppressant use if reasonable alternatives are available. Neurologists should be vigilant for symptoms suggestive of PML and could consider performing an MRI at least every six months in JCV seropositive patients.

Antinatalizumab antibodies, which can develop particularly with prior natalizumab use, and history of anaphylaxis increase the risk of allergic reactions to natalizumab, Dr. Fox noted. Liver enzyme screening at baseline and close monitoring for patients with a history of liver disease can mitigate the risk of elevated liver enzymes.

Fingolimod
Fingolimod, particularly the first dose of the drug, entails a risk of cardiac events, and concomitant medications can increase this risk. Obtaining a cardiac history is advisable before patients start fingolimod. In addition, neurologists should perform baseline EKG, first-dose observation, and a post first-dose EKG for the patient. A standard observation lasts for six hours and includes frequent monitoring of vital signs. A 24-hour observation is indicated in patients with certain risk factors.

Fingolimod also carries a risk of macular edema that may be higher in older people or those with a history of diabetes or uveitis. Neurologists therefore should perform optical coherence tomography at baseline and at three months, said Dr. Fox. Patients with visual symptoms should be evaluated promptly for possible macular edema.

Because the drug is associated with a risk of herpes virus infections, patients should be screened for varicella zoster serology, even if they have a history of chicken pox. Seronegative patients require vaccination before starting fingolimod. Other risks include lymphopenia and leukopenia, and neurologists can monitor for these outcomes through intermittent complete blood count testing. Repeated liver function panels may mitigate the risk of increased liver enzymes, and headaches and back pain can be treated symptomatically.

Teriflunomide
Teratogenesis may be the biggest concern for patients treated with teriflunomide, which is labeled as pregnancy category X. Alternative therapies could be considered for people of childbearing potential, said Dr. Fox. Patients who receive teriflunomide should use contraception. Certain treatments can accelerate washout if a patient wants to become pregnant or inadvertently becomes pregnant while taking teriflunomide.

Teriflunomide may increase liver enzymes, therefore monitoring is appropriate. The drug is relatively contraindicated for patients with previous liver injury secondary to medications, liver disease, or tuberculosis, added Dr. Fox.

Dimethyl Fumarate
Flushing occurs in one-third of patients taking dimethyl fumarate. This side effect is benign and typically passes in 20 minutes. Taking aspirin daily can prevent flushing or reduce its severity.

One-third of patients may experience gastrointestinal side effects, including nausea, vomiting, diarrhea, and abdominal pain. The symptoms typically improve after one month. Administering the drug with food, titrating the dose slowly, and providing symptomatic treatments may help.

Dimethyl fumarate also is associated with lymphopenia, which typically takes around 12 months to develop. It is reasonable to monitor patients for lymphopenia, particularly at 12 months, and for infections, said Dr. Fox.

The drug also may be associated with a risk of PML. Four cases of PML have been reported from a total experience of approximately 170,000 patient years. Patients with PML had been receiving a formulation of dimethyl fumarate used to treat psoriasis, and some had prior immunosuppressant use and prolonged lymphopenia. After the ECTRIMS meeting, the manufacturer reported a case of PML in a patient with MS receiving dimethyl fumarate who had low lymphocyte counts for 3.5 years. Compared with natalizumab, dimethyl fumarate is associated with a lower risk of PML. “Nonetheless, it’s something that we’re keeping in the back of our mind and watching for,” said Dr. Fox. Monitoring for severely reduced lymphocyte counts may mitigate the risk of PML, he concluded.

—Erik Greb

BOSTON—The emergence of many new disease-modifying therapies in the past 10 years has made it more challenging to choose a drug for a patient with multiple sclerosis (MS), according to an overview provided at the 2014 Joint ACTRIMS–ECTRIMS Meeting. In the United States, 12 FDA-approved therapies, including oral medications, are available for the long-term treatment of MS. These medications’ efficacy, tolerability, and safety differ widely, and patient-specific risk factors can be an important guide for choosing the appropriate treatment, said Robert Fox, MD, Vice Chair for Research at the Cleveland Clinic.

Head-to-head comparisons indicate great similarity among injectable MS therapies, which generally reduce annualized relapse rate by about 30%. The choice of an injectable therapy should be influenced by the expected side effect profile, the patient’s risk factors, patient preference about the frequency of administration, and the clinician’s comfort with the drug, said Dr. Fox. Risk stratification and mitigation should continue over time because risk factors can change, thus altering an individual’s risk for a complication.

Interferon and Glatiramer Acetate Interferon and glatiramer acetate are considered relatively safe medications, but they still require risk evaluation and mitigation, Dr. Fox said. Nonsteroidal anti-inflammatory agents and hydration can mitigate interferon’s flu-like side effects, and monitoring can reduce the drug’s associated risks of increased liver enzymes and leukopenia. Screening patients for headache, pain syndromes, and depression is also warranted before and during interferon treatment.

Glatiramer acetate entails risks of erythema, lipoatrophy, induration, and immediate post injection systemic reaction. Education and proper injection technique can mitigate the risk of skin reactions, and “education is of high importance for the post injection systemic reaction and can help avoid needless trips to the emergency room,” said Dr. Fox.

Natalizumab
Researchers have identified three main factors that can stratify the risk for progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab: John Cunningham virus (JCV) infection, prior immunosuppressant use, and duration of natalizumab treatment. Patient counseling and decision making depend greatly on which risk factors the patient has, said Dr. Fox.

Natalizumab is considered relatively safe for patients who are JCV negative, but seroconversion may occur over time. Neurologists can consider other therapies for individuals who are JCV positive, but if good alternatives are not available, the clinician may consider limiting natalizumab treatment to one to two years. Natalizumab should be avoided for patients with prior immunosuppressant use if reasonable alternatives are available. Neurologists should be vigilant for symptoms suggestive of PML and could consider performing an MRI at least every six months in JCV seropositive patients.

Antinatalizumab antibodies, which can develop particularly with prior natalizumab use, and history of anaphylaxis increase the risk of allergic reactions to natalizumab, Dr. Fox noted. Liver enzyme screening at baseline and close monitoring for patients with a history of liver disease can mitigate the risk of elevated liver enzymes.

Fingolimod
Fingolimod, particularly the first dose of the drug, entails a risk of cardiac events, and concomitant medications can increase this risk. Obtaining a cardiac history is advisable before patients start fingolimod. In addition, neurologists should perform baseline EKG, first-dose observation, and a post first-dose EKG for the patient. A standard observation lasts for six hours and includes frequent monitoring of vital signs. A 24-hour observation is indicated in patients with certain risk factors.

Fingolimod also carries a risk of macular edema that may be higher in older people or those with a history of diabetes or uveitis. Neurologists therefore should perform optical coherence tomography at baseline and at three months, said Dr. Fox. Patients with visual symptoms should be evaluated promptly for possible macular edema.

Because the drug is associated with a risk of herpes virus infections, patients should be screened for varicella zoster serology, even if they have a history of chicken pox. Seronegative patients require vaccination before starting fingolimod. Other risks include lymphopenia and leukopenia, and neurologists can monitor for these outcomes through intermittent complete blood count testing. Repeated liver function panels may mitigate the risk of increased liver enzymes, and headaches and back pain can be treated symptomatically.

Teriflunomide
Teratogenesis may be the biggest concern for patients treated with teriflunomide, which is labeled as pregnancy category X. Alternative therapies could be considered for people of childbearing potential, said Dr. Fox. Patients who receive teriflunomide should use contraception. Certain treatments can accelerate washout if a patient wants to become pregnant or inadvertently becomes pregnant while taking teriflunomide.

Teriflunomide may increase liver enzymes, therefore monitoring is appropriate. The drug is relatively contraindicated for patients with previous liver injury secondary to medications, liver disease, or tuberculosis, added Dr. Fox.

Dimethyl Fumarate
Flushing occurs in one-third of patients taking dimethyl fumarate. This side effect is benign and typically passes in 20 minutes. Taking aspirin daily can prevent flushing or reduce its severity.

One-third of patients may experience gastrointestinal side effects, including nausea, vomiting, diarrhea, and abdominal pain. The symptoms typically improve after one month. Administering the drug with food, titrating the dose slowly, and providing symptomatic treatments may help.

Dimethyl fumarate also is associated with lymphopenia, which typically takes around 12 months to develop. It is reasonable to monitor patients for lymphopenia, particularly at 12 months, and for infections, said Dr. Fox.

The drug also may be associated with a risk of PML. Four cases of PML have been reported from a total experience of approximately 170,000 patient years. Patients with PML had been receiving a formulation of dimethyl fumarate used to treat psoriasis, and some had prior immunosuppressant use and prolonged lymphopenia. After the ECTRIMS meeting, the manufacturer reported a case of PML in a patient with MS receiving dimethyl fumarate who had low lymphocyte counts for 3.5 years. Compared with natalizumab, dimethyl fumarate is associated with a lower risk of PML. “Nonetheless, it’s something that we’re keeping in the back of our mind and watching for,” said Dr. Fox. Monitoring for severely reduced lymphocyte counts may mitigate the risk of PML, he concluded.

—Erik Greb