Multiple Sclerosis

BERLIN – The risk of cancer – and breast cancer in particular – was not elevated above background levels in a large cohort of multiple sclerosis patients taking disease-modifying therapies.

Those findings from the large Nordic cohort study COMBAT-MS stand in contrast to previous work showing an elevated cancer risk for some monoclonal antibodies.

After statistical adjustment and use of rituximab (Rituxan) as the standard, the hazard ratio (HR) for any malignancy with fingolimod (Gilenya) was 1.74 (95% confidence interval, 0.92-3.28). For natalizumab (Tysabri), the malignancy HR was 1.06 (95% CI, 0.53-2.10), said Peter Alping, a PhD student in the department of clinical neuroscience at the Karolinska Institute, Stockholm.

Only limited data exist for real-world multiple sclerosis (MS) cohorts who have been exposed to novel disease-modifying therapies, said Mr. Alping, presenting the findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Rituximab has been studied in patients with rheumatoid arthritis, but the treatment regimens differ, as do patient characteristics, he noted. However, surveillance for risk of malignancy is important in these therapies, he said, “since modern disease-modifying therapies exert a more profound effect on the immune system, and we know that the immune system is vital in fighting and preventing cancers.”

The anti-CD20 monoclonal antibody ocrelizumab was studied in the ORATORIO trial. “There, they saw an imbalance in the numbers of breast cancers between the ocrelizumab and placebo groups,” said Mr. Alping, with raw data showing four breast cancers in the ocrelizumab population. However, this would translate to 26.1 cancers per 10,000 person-years, as opposed to the zero breast cancers seen in the placebo group (N Engl J Med. 2017;376:209-20).

“To what degree is cancer risk a concern with novel [disease-modifying therapy] use in MS?” Mr. Alping asked.

To answer the question, he and his colleagues from the Karolinska Institute sought to compare the risk of cancer in MS patients who were treated with rituximab, fingolimod, and natalizumab.

To do this, they conducted a nationwide cohort study using the Swedish MS registry, looking at treatment episodes between 2011 and 2016. In Sweden, the MS registry is also linked to the overall patient registry, as well as registries for cancer and prescription drug use. In addition, patient data are linked to national census data.

Mr. Alping and his colleagues looked at data for the first instance of use for an MS patient of rituximab, natalizumab, and/or fingolimod between the years 2011 and 2016. Then, they matched patient records from the general population by age, sex, and geographic location, enrolling the matched controls at the same time point as the MS match entered the study.

Patients treated with mitoxantrone, those who emigrated, and those who died during the study period were excluded from the study.

The statistical analysis, Mr. Alping said, used an ever-treated approach and didn’t attempt to weight exposure duration or dose. However, statistical adjustments were made for patient and control demographics and medical history, for any previous history of cancer, and for MS disease characteristics.

At baseline, 1,558 patients had been treated with fingolimod, 1,761 with natalizumab, and 3,012 with rituximab. A little less than one-third of the patients (26.3%-31.6%) were male, and the mean age was 35-43 years. Most patients (66%-86%) had undergone one or two previous therapies. The mean Expanded Disability Status Scale (EDSS) score was 2.20-2.88. Few patients (0.9%-1.7%) had any history of previous cancer.

Overall, the incidence of cancer in the MS cohort ranged from 23.09 per 10,000 person-years for rituximab ever-takers to 46.28 for those who had ever taken fingolimod. Among the general population, rates of any malignancy were 29.62 per 10,000 person-years.

Looking just at breast cancer, rates in the MS cohort ranged from 2.19 to 2.92/10,000 person-years. For the general population, the rate was 12.07/10,000 person-years.

However, using a Cox regression analysis employing MS-specific covariates and using rituximab as the reference, Mr. Alping and his colleagues calculated an inverse proportion-weighted hazard ratio for any malignancy under the various treatment conditions. Using this analysis, the HR for any cancer with fingolimod was 1.74 (95% CI, 0.92-3.28). For natalizumab, the malignancy HR was 1.06 (95% CI, 0.53-2.10).

Among just women taking rituximab, 2,274 therapy starts occurred, and one breast cancer was seen in 4,050 person-years. This yielded an incidence of 2.32 cancers per 10,000 person-years (95% CI, 0.06-12.9). This contrasts with the adjusted incidence rate in the general female population of 11.06 breast cancers per 10,000 person-years.

Looking at all the therapy episodes captured in the cohort study, there were 6,660 incidences of therapy initiation, and 52 malignancies were seen over 17,283 person-years, Mr. Alping said.

“For malignant cancer of any type, we found no increased risk for rituximab, compared to fingolimod and natalizumab,” Mr. Alping said, pointing to the wide confidence intervals in all the adjusted data. The incidence of breast cancer in women who have taken rituximab, he said, is “comparable to, or possibly lower than, that of the general female population, and lower than the incidence rate reported in the ORATORIO trial for ocrelizumab.

“The overall cancer risk and risk of breast cancer might not be major concerns short term when treating MS patients with rituximab relative to other disease-modifying therapies,” he said.

The study was partially funded by the Patient-Centered Outcomes Research Institute. Mr. Alping reported no conflicts of interest. One study author reported relationships with several pharmaceutical companies.

koakes@mdedge.com

SOURCE: Alping P et al. Mult Scler. 2018;24(Suppl 2):36. Abstract 89.

BERLIN – The risk of cancer – and breast cancer in particular – was not elevated above background levels in a large cohort of multiple sclerosis patients taking disease-modifying therapies.

Those findings from the large Nordic cohort study COMBAT-MS stand in contrast to previous work showing an elevated cancer risk for some monoclonal antibodies.

After statistical adjustment and use of rituximab (Rituxan) as the standard, the hazard ratio (HR) for any malignancy with fingolimod (Gilenya) was 1.74 (95% confidence interval, 0.92-3.28). For natalizumab (Tysabri), the malignancy HR was 1.06 (95% CI, 0.53-2.10), said Peter Alping, a PhD student in the department of clinical neuroscience at the Karolinska Institute, Stockholm.

Only limited data exist for real-world multiple sclerosis (MS) cohorts who have been exposed to novel disease-modifying therapies, said Mr. Alping, presenting the findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Rituximab has been studied in patients with rheumatoid arthritis, but the treatment regimens differ, as do patient characteristics, he noted. However, surveillance for risk of malignancy is important in these therapies, he said, “since modern disease-modifying therapies exert a more profound effect on the immune system, and we know that the immune system is vital in fighting and preventing cancers.”

The anti-CD20 monoclonal antibody ocrelizumab was studied in the ORATORIO trial. “There, they saw an imbalance in the numbers of breast cancers between the ocrelizumab and placebo groups,” said Mr. Alping, with raw data showing four breast cancers in the ocrelizumab population. However, this would translate to 26.1 cancers per 10,000 person-years, as opposed to the zero breast cancers seen in the placebo group (N Engl J Med. 2017;376:209-20).

“To what degree is cancer risk a concern with novel [disease-modifying therapy] use in MS?” Mr. Alping asked.

To answer the question, he and his colleagues from the Karolinska Institute sought to compare the risk of cancer in MS patients who were treated with rituximab, fingolimod, and natalizumab.

To do this, they conducted a nationwide cohort study using the Swedish MS registry, looking at treatment episodes between 2011 and 2016. In Sweden, the MS registry is also linked to the overall patient registry, as well as registries for cancer and prescription drug use. In addition, patient data are linked to national census data.

Mr. Alping and his colleagues looked at data for the first instance of use for an MS patient of rituximab, natalizumab, and/or fingolimod between the years 2011 and 2016. Then, they matched patient records from the general population by age, sex, and geographic location, enrolling the matched controls at the same time point as the MS match entered the study.

Patients treated with mitoxantrone, those who emigrated, and those who died during the study period were excluded from the study.

The statistical analysis, Mr. Alping said, used an ever-treated approach and didn’t attempt to weight exposure duration or dose. However, statistical adjustments were made for patient and control demographics and medical history, for any previous history of cancer, and for MS disease characteristics.

At baseline, 1,558 patients had been treated with fingolimod, 1,761 with natalizumab, and 3,012 with rituximab. A little less than one-third of the patients (26.3%-31.6%) were male, and the mean age was 35-43 years. Most patients (66%-86%) had undergone one or two previous therapies. The mean Expanded Disability Status Scale (EDSS) score was 2.20-2.88. Few patients (0.9%-1.7%) had any history of previous cancer.

Overall, the incidence of cancer in the MS cohort ranged from 23.09 per 10,000 person-years for rituximab ever-takers to 46.28 for those who had ever taken fingolimod. Among the general population, rates of any malignancy were 29.62 per 10,000 person-years.

Looking just at breast cancer, rates in the MS cohort ranged from 2.19 to 2.92/10,000 person-years. For the general population, the rate was 12.07/10,000 person-years.

However, using a Cox regression analysis employing MS-specific covariates and using rituximab as the reference, Mr. Alping and his colleagues calculated an inverse proportion-weighted hazard ratio for any malignancy under the various treatment conditions. Using this analysis, the HR for any cancer with fingolimod was 1.74 (95% CI, 0.92-3.28). For natalizumab, the malignancy HR was 1.06 (95% CI, 0.53-2.10).

Among just women taking rituximab, 2,274 therapy starts occurred, and one breast cancer was seen in 4,050 person-years. This yielded an incidence of 2.32 cancers per 10,000 person-years (95% CI, 0.06-12.9). This contrasts with the adjusted incidence rate in the general female population of 11.06 breast cancers per 10,000 person-years.

Looking at all the therapy episodes captured in the cohort study, there were 6,660 incidences of therapy initiation, and 52 malignancies were seen over 17,283 person-years, Mr. Alping said.

“For malignant cancer of any type, we found no increased risk for rituximab, compared to fingolimod and natalizumab,” Mr. Alping said, pointing to the wide confidence intervals in all the adjusted data. The incidence of breast cancer in women who have taken rituximab, he said, is “comparable to, or possibly lower than, that of the general female population, and lower than the incidence rate reported in the ORATORIO trial for ocrelizumab.

“The overall cancer risk and risk of breast cancer might not be major concerns short term when treating MS patients with rituximab relative to other disease-modifying therapies,” he said.

The study was partially funded by the Patient-Centered Outcomes Research Institute. Mr. Alping reported no conflicts of interest. One study author reported relationships with several pharmaceutical companies.

koakes@mdedge.com

SOURCE: Alping P et al. Mult Scler. 2018;24(Suppl 2):36. Abstract 89.

BERLIN – The risk of cancer – and breast cancer in particular – was not elevated above background levels in a large cohort of multiple sclerosis patients taking disease-modifying therapies.

Those findings from the large Nordic cohort study COMBAT-MS stand in contrast to previous work showing an elevated cancer risk for some monoclonal antibodies.

After statistical adjustment and use of rituximab (Rituxan) as the standard, the hazard ratio (HR) for any malignancy with fingolimod (Gilenya) was 1.74 (95% confidence interval, 0.92-3.28). For natalizumab (Tysabri), the malignancy HR was 1.06 (95% CI, 0.53-2.10), said Peter Alping, a PhD student in the department of clinical neuroscience at the Karolinska Institute, Stockholm.

Only limited data exist for real-world multiple sclerosis (MS) cohorts who have been exposed to novel disease-modifying therapies, said Mr. Alping, presenting the findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Rituximab has been studied in patients with rheumatoid arthritis, but the treatment regimens differ, as do patient characteristics, he noted. However, surveillance for risk of malignancy is important in these therapies, he said, “since modern disease-modifying therapies exert a more profound effect on the immune system, and we know that the immune system is vital in fighting and preventing cancers.”

The anti-CD20 monoclonal antibody ocrelizumab was studied in the ORATORIO trial. “There, they saw an imbalance in the numbers of breast cancers between the ocrelizumab and placebo groups,” said Mr. Alping, with raw data showing four breast cancers in the ocrelizumab population. However, this would translate to 26.1 cancers per 10,000 person-years, as opposed to the zero breast cancers seen in the placebo group (N Engl J Med. 2017;376:209-20).

“To what degree is cancer risk a concern with novel [disease-modifying therapy] use in MS?” Mr. Alping asked.

To answer the question, he and his colleagues from the Karolinska Institute sought to compare the risk of cancer in MS patients who were treated with rituximab, fingolimod, and natalizumab.

To do this, they conducted a nationwide cohort study using the Swedish MS registry, looking at treatment episodes between 2011 and 2016. In Sweden, the MS registry is also linked to the overall patient registry, as well as registries for cancer and prescription drug use. In addition, patient data are linked to national census data.

Mr. Alping and his colleagues looked at data for the first instance of use for an MS patient of rituximab, natalizumab, and/or fingolimod between the years 2011 and 2016. Then, they matched patient records from the general population by age, sex, and geographic location, enrolling the matched controls at the same time point as the MS match entered the study.

Patients treated with mitoxantrone, those who emigrated, and those who died during the study period were excluded from the study.

The statistical analysis, Mr. Alping said, used an ever-treated approach and didn’t attempt to weight exposure duration or dose. However, statistical adjustments were made for patient and control demographics and medical history, for any previous history of cancer, and for MS disease characteristics.

At baseline, 1,558 patients had been treated with fingolimod, 1,761 with natalizumab, and 3,012 with rituximab. A little less than one-third of the patients (26.3%-31.6%) were male, and the mean age was 35-43 years. Most patients (66%-86%) had undergone one or two previous therapies. The mean Expanded Disability Status Scale (EDSS) score was 2.20-2.88. Few patients (0.9%-1.7%) had any history of previous cancer.

Overall, the incidence of cancer in the MS cohort ranged from 23.09 per 10,000 person-years for rituximab ever-takers to 46.28 for those who had ever taken fingolimod. Among the general population, rates of any malignancy were 29.62 per 10,000 person-years.

Looking just at breast cancer, rates in the MS cohort ranged from 2.19 to 2.92/10,000 person-years. For the general population, the rate was 12.07/10,000 person-years.

However, using a Cox regression analysis employing MS-specific covariates and using rituximab as the reference, Mr. Alping and his colleagues calculated an inverse proportion-weighted hazard ratio for any malignancy under the various treatment conditions. Using this analysis, the HR for any cancer with fingolimod was 1.74 (95% CI, 0.92-3.28). For natalizumab, the malignancy HR was 1.06 (95% CI, 0.53-2.10).

Among just women taking rituximab, 2,274 therapy starts occurred, and one breast cancer was seen in 4,050 person-years. This yielded an incidence of 2.32 cancers per 10,000 person-years (95% CI, 0.06-12.9). This contrasts with the adjusted incidence rate in the general female population of 11.06 breast cancers per 10,000 person-years.

Looking at all the therapy episodes captured in the cohort study, there were 6,660 incidences of therapy initiation, and 52 malignancies were seen over 17,283 person-years, Mr. Alping said.

“For malignant cancer of any type, we found no increased risk for rituximab, compared to fingolimod and natalizumab,” Mr. Alping said, pointing to the wide confidence intervals in all the adjusted data. The incidence of breast cancer in women who have taken rituximab, he said, is “comparable to, or possibly lower than, that of the general female population, and lower than the incidence rate reported in the ORATORIO trial for ocrelizumab.

“The overall cancer risk and risk of breast cancer might not be major concerns short term when treating MS patients with rituximab relative to other disease-modifying therapies,” he said.

The study was partially funded by the Patient-Centered Outcomes Research Institute. Mr. Alping reported no conflicts of interest. One study author reported relationships with several pharmaceutical companies.

koakes@mdedge.com

SOURCE: Alping P et al. Mult Scler. 2018;24(Suppl 2):36. Abstract 89.

Infusion of allogeneic BK virus–specific T cells may be an effective treatment for patients with progressive multifocal leukoencephalopathy (PML), according to investigators from the University of Texas MD Anderson Cancer Center, Houston.

The infusion cleared JC virus from the cerebrospinal fluid (CSF) of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of MD Anderson’s department of stem cell transplantation and cellular therapy and colleagues. One of the patients completely recovered and returned to work.

Jochen Sand/Thinkstock

“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators wrote in the New England Journal of Medicine. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions.

“Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators wrote. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”

This hypothesis proved accurate. The investigators infused three PML patients with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib (Jakafi) therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.

T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees: The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about 8 months later.

No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within 4 weeks of treatment. Still, the investigators were optimistic about future potential.

“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”

The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.

SOURCE: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51

This article was updated 3/22/19.

Infusion of allogeneic BK virus–specific T cells may be an effective treatment for patients with progressive multifocal leukoencephalopathy (PML), according to investigators from the University of Texas MD Anderson Cancer Center, Houston.

The infusion cleared JC virus from the cerebrospinal fluid (CSF) of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of MD Anderson’s department of stem cell transplantation and cellular therapy and colleagues. One of the patients completely recovered and returned to work.

Jochen Sand/Thinkstock

“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators wrote in the New England Journal of Medicine. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions.

“Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators wrote. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”

This hypothesis proved accurate. The investigators infused three PML patients with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib (Jakafi) therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.

T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees: The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about 8 months later.

No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within 4 weeks of treatment. Still, the investigators were optimistic about future potential.

“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”

The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.

SOURCE: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51

This article was updated 3/22/19.

Infusion of allogeneic BK virus–specific T cells may be an effective treatment for patients with progressive multifocal leukoencephalopathy (PML), according to investigators from the University of Texas MD Anderson Cancer Center, Houston.

The infusion cleared JC virus from the cerebrospinal fluid (CSF) of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of MD Anderson’s department of stem cell transplantation and cellular therapy and colleagues. One of the patients completely recovered and returned to work.

Jochen Sand/Thinkstock

“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators wrote in the New England Journal of Medicine. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions.

“Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators wrote. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”

This hypothesis proved accurate. The investigators infused three PML patients with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib (Jakafi) therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.

T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees: The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about 8 months later.

No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within 4 weeks of treatment. Still, the investigators were optimistic about future potential.

“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”

The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.

SOURCE: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51

This article was updated 3/22/19.

New evidence provides estimates of the pregnancy rates for American women with multiple sclerosis (MS), their complication rates, and the rates of relapse and disease-modifying drug treatment during different phases before and after pregnancy.

The two new studies, conducted by Maria K. Houtchens, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, and her colleagues involved retrospective mining of U.S. commercial health plan data in the IQVIA Real-World Data Adjudicated Claims–U.S. database between Jan. 1, 2006, and June 30, 2015.

The mean age of pregnant women in the nine annual cohorts during that period was just over 32 years for those with MS and just over 29 years for those without. The percentage of women without MS who had a pregnancy-related claim in the database declined from 8.83% in 2006 to 7.75% in 2014 after adjusting for age, region, payer, and Charlson Comorbidity Index score, whereas the percentage increased in women with MS during the same period, from 7.91% to 9.47%. The investigators matched 2,115 women with MS and 2,115 without MS who had live births for a variety of variables and found that women with MS had higher rates of premature labor (31.4% vs. 27.4%; P = .005), infection in pregnancy (13.3% vs. 10.9%; P = .016), maternal cardiovascular disease (3.0% vs. 1.9%; P = .028), anemia or acquired coagulation disorder (2.5% vs. 1.3%; P = .007), neurologic complications in pregnancy (1.6% vs. 0.6%; P = .005), and sexually transmitted diseases in pregnancy (0.4% vs. 0%; P = .045). During labor and delivery, women with MS who had a live birth more often had a claim for acquired damage to the fetus (27.8% vs. 23.5%; P = .002) and congenital fetal malformations (13.2% vs. 10.3%; P = .004) than did women without MS.

In the second study, Dr. Houtchens and two coauthors from the first study of the database reported on a set of 2,158 women who had a live birth during the study period and had 1 year of continuous insurance eligibility before and after pregnancy. The odds for having an MS relapse declined during pregnancy (odds ratio, 0.623; 95% confidence interval, 0.521-0.744), rose during the 6-week postpartum puerperium (OR, 1.710; 95% CI, 1.358-2.152), and leveled off during the last three postpartum quarters to remain at a higher level than before pregnancy (OR, 1.216; 95% CI, 1.052-1.406). Disease-modifying drug treatment followed the same pattern with 20% using it before pregnancy, dropping to about 2% in the second trimester, and peaking in about a quarter of all patients 9-12 months post partum.

jevans@mdedge.com

SOURCES: Houtchens MK et al. Neurology. 2018 Sep 28. doi: 10.1212/WNL.0000000000006382; Houtchens MK et al. Neurology. 2018 Sep 28. doi: 10.1212/WNL.0000000000006384.

New evidence provides estimates of the pregnancy rates for American women with multiple sclerosis (MS), their complication rates, and the rates of relapse and disease-modifying drug treatment during different phases before and after pregnancy.

The two new studies, conducted by Maria K. Houtchens, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, and her colleagues involved retrospective mining of U.S. commercial health plan data in the IQVIA Real-World Data Adjudicated Claims–U.S. database between Jan. 1, 2006, and June 30, 2015.

The mean age of pregnant women in the nine annual cohorts during that period was just over 32 years for those with MS and just over 29 years for those without. The percentage of women without MS who had a pregnancy-related claim in the database declined from 8.83% in 2006 to 7.75% in 2014 after adjusting for age, region, payer, and Charlson Comorbidity Index score, whereas the percentage increased in women with MS during the same period, from 7.91% to 9.47%. The investigators matched 2,115 women with MS and 2,115 without MS who had live births for a variety of variables and found that women with MS had higher rates of premature labor (31.4% vs. 27.4%; P = .005), infection in pregnancy (13.3% vs. 10.9%; P = .016), maternal cardiovascular disease (3.0% vs. 1.9%; P = .028), anemia or acquired coagulation disorder (2.5% vs. 1.3%; P = .007), neurologic complications in pregnancy (1.6% vs. 0.6%; P = .005), and sexually transmitted diseases in pregnancy (0.4% vs. 0%; P = .045). During labor and delivery, women with MS who had a live birth more often had a claim for acquired damage to the fetus (27.8% vs. 23.5%; P = .002) and congenital fetal malformations (13.2% vs. 10.3%; P = .004) than did women without MS.

In the second study, Dr. Houtchens and two coauthors from the first study of the database reported on a set of 2,158 women who had a live birth during the study period and had 1 year of continuous insurance eligibility before and after pregnancy. The odds for having an MS relapse declined during pregnancy (odds ratio, 0.623; 95% confidence interval, 0.521-0.744), rose during the 6-week postpartum puerperium (OR, 1.710; 95% CI, 1.358-2.152), and leveled off during the last three postpartum quarters to remain at a higher level than before pregnancy (OR, 1.216; 95% CI, 1.052-1.406). Disease-modifying drug treatment followed the same pattern with 20% using it before pregnancy, dropping to about 2% in the second trimester, and peaking in about a quarter of all patients 9-12 months post partum.

jevans@mdedge.com

SOURCES: Houtchens MK et al. Neurology. 2018 Sep 28. doi: 10.1212/WNL.0000000000006382; Houtchens MK et al. Neurology. 2018 Sep 28. doi: 10.1212/WNL.0000000000006384.

New evidence provides estimates of the pregnancy rates for American women with multiple sclerosis (MS), their complication rates, and the rates of relapse and disease-modifying drug treatment during different phases before and after pregnancy.

The two new studies, conducted by Maria K. Houtchens, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, and her colleagues involved retrospective mining of U.S. commercial health plan data in the IQVIA Real-World Data Adjudicated Claims–U.S. database between Jan. 1, 2006, and June 30, 2015.

The mean age of pregnant women in the nine annual cohorts during that period was just over 32 years for those with MS and just over 29 years for those without. The percentage of women without MS who had a pregnancy-related claim in the database declined from 8.83% in 2006 to 7.75% in 2014 after adjusting for age, region, payer, and Charlson Comorbidity Index score, whereas the percentage increased in women with MS during the same period, from 7.91% to 9.47%. The investigators matched 2,115 women with MS and 2,115 without MS who had live births for a variety of variables and found that women with MS had higher rates of premature labor (31.4% vs. 27.4%; P = .005), infection in pregnancy (13.3% vs. 10.9%; P = .016), maternal cardiovascular disease (3.0% vs. 1.9%; P = .028), anemia or acquired coagulation disorder (2.5% vs. 1.3%; P = .007), neurologic complications in pregnancy (1.6% vs. 0.6%; P = .005), and sexually transmitted diseases in pregnancy (0.4% vs. 0%; P = .045). During labor and delivery, women with MS who had a live birth more often had a claim for acquired damage to the fetus (27.8% vs. 23.5%; P = .002) and congenital fetal malformations (13.2% vs. 10.3%; P = .004) than did women without MS.

In the second study, Dr. Houtchens and two coauthors from the first study of the database reported on a set of 2,158 women who had a live birth during the study period and had 1 year of continuous insurance eligibility before and after pregnancy. The odds for having an MS relapse declined during pregnancy (odds ratio, 0.623; 95% confidence interval, 0.521-0.744), rose during the 6-week postpartum puerperium (OR, 1.710; 95% CI, 1.358-2.152), and leveled off during the last three postpartum quarters to remain at a higher level than before pregnancy (OR, 1.216; 95% CI, 1.052-1.406). Disease-modifying drug treatment followed the same pattern with 20% using it before pregnancy, dropping to about 2% in the second trimester, and peaking in about a quarter of all patients 9-12 months post partum.

jevans@mdedge.com

SOURCES: Houtchens MK et al. Neurology. 2018 Sep 28. doi: 10.1212/WNL.0000000000006382; Houtchens MK et al. Neurology. 2018 Sep 28. doi: 10.1212/WNL.0000000000006384.

Recent research has pointed to a role for measuring neurofilament light (Nf-L) chain levels to predict disease severity in multiple sclerosis (MS). Several papers presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis in Berlin will describe new developments on the topic.

A highlighted session on the congress’s last day explores recent development in progressive MS. While much of the research on using Nf-L as a biomarker focuses on relapsing remitting MS, researchers from University Hospital, Basel, Switzerland, and Novartis used data from placebo-controlled, phase 3 trials of fingolimod (INFORMS) and siponimod (EXPAND) to learn how to use biomarkers to track brain atrophy in patients with primary and secondary progressive MS. Hear the results from lead researcher Jens Kuhle, MD, in Hall A at 10:30 a.m. (local time) on Friday, Oct. 12.

Nf-L also is being looked at as a way to suss out treatment failure. Researchers with the Swiss MS Cohort Study will present their study of Nf-L as a biomarker of suboptimal treatment response in patients with relapsing remitting MS on established disease-modifying therapy. Their findings will be presented by Özguer Yaldizli, MD, also of University Hospital, also in Hall A, at 8:30 a.m. (local time) on Friday, Oct. 12.

Follow #ECTRIMS2018 on Twitter to see live highlights and perspective from researchers and meeting attendees.

dfulton@mdedge.com

Recent research has pointed to a role for measuring neurofilament light (Nf-L) chain levels to predict disease severity in multiple sclerosis (MS). Several papers presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis in Berlin will describe new developments on the topic.

A highlighted session on the congress’s last day explores recent development in progressive MS. While much of the research on using Nf-L as a biomarker focuses on relapsing remitting MS, researchers from University Hospital, Basel, Switzerland, and Novartis used data from placebo-controlled, phase 3 trials of fingolimod (INFORMS) and siponimod (EXPAND) to learn how to use biomarkers to track brain atrophy in patients with primary and secondary progressive MS. Hear the results from lead researcher Jens Kuhle, MD, in Hall A at 10:30 a.m. (local time) on Friday, Oct. 12.

Nf-L also is being looked at as a way to suss out treatment failure. Researchers with the Swiss MS Cohort Study will present their study of Nf-L as a biomarker of suboptimal treatment response in patients with relapsing remitting MS on established disease-modifying therapy. Their findings will be presented by Özguer Yaldizli, MD, also of University Hospital, also in Hall A, at 8:30 a.m. (local time) on Friday, Oct. 12.

Follow #ECTRIMS2018 on Twitter to see live highlights and perspective from researchers and meeting attendees.

dfulton@mdedge.com

Recent research has pointed to a role for measuring neurofilament light (Nf-L) chain levels to predict disease severity in multiple sclerosis (MS). Several papers presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis in Berlin will describe new developments on the topic.

A highlighted session on the congress’s last day explores recent development in progressive MS. While much of the research on using Nf-L as a biomarker focuses on relapsing remitting MS, researchers from University Hospital, Basel, Switzerland, and Novartis used data from placebo-controlled, phase 3 trials of fingolimod (INFORMS) and siponimod (EXPAND) to learn how to use biomarkers to track brain atrophy in patients with primary and secondary progressive MS. Hear the results from lead researcher Jens Kuhle, MD, in Hall A at 10:30 a.m. (local time) on Friday, Oct. 12.

Nf-L also is being looked at as a way to suss out treatment failure. Researchers with the Swiss MS Cohort Study will present their study of Nf-L as a biomarker of suboptimal treatment response in patients with relapsing remitting MS on established disease-modifying therapy. Their findings will be presented by Özguer Yaldizli, MD, also of University Hospital, also in Hall A, at 8:30 a.m. (local time) on Friday, Oct. 12.

Follow #ECTRIMS2018 on Twitter to see live highlights and perspective from researchers and meeting attendees.

dfulton@mdedge.com

The revised McDonald criteria, issued less than a year ago in December 2017, should allow for earlier diagnosis and treatment of multiple sclerosis, but also could be leading to overdiagnosis and misdiagnosis.

A recent study published in JAMA Neurology found that sensitivity for the 2017 criteria was greater (68% vs. 36% for the 2010 criteria) but specificity was not (61% vs. 85%, respectively), based on a study of several hundred patients in the Netherlands with clinically isolated syndrome.

The ins and outs and pros and cons of the revised McDonald criteria will be discussed in two sessions at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

A highlighted session on Saturday, Oct. 10, at 2:30 p.m. (local time) entitled “Burning Debate: The new McDonald diagnostic criteria are controversial making them difficult to use in clinical practice” aims to shed some light. After an introduction from Emmanuelle Waubant, MD, professor of neurology at the University of California, San Francisco, the topic will be debated by Jiwon Oh, MD, of the University of Toronto and Frauke Zipp, MD, of the University of Mainz (Germany). The experts will take questions from the audience as well as via Twitter. Ask your questions using the meeting hashtag #ECTRIMS2018. Find the session in Hall B.

Five new papers on the impact of the revised criteria will be presented in Hall A on Sunday, Oct. 11, at 8:30 a.m. (local time). Among the investigators presenting are Roos M. van der Vuurst de Vries, MD, from the department of neurology at Erasmus Medical Center in Rotterdam, the Netherlands, who authored the recent JAMA Neurology paper, and Wallace Brownlee, MD, of University College London.

dfulton@mdedge.com

The revised McDonald criteria, issued less than a year ago in December 2017, should allow for earlier diagnosis and treatment of multiple sclerosis, but also could be leading to overdiagnosis and misdiagnosis.

A recent study published in JAMA Neurology found that sensitivity for the 2017 criteria was greater (68% vs. 36% for the 2010 criteria) but specificity was not (61% vs. 85%, respectively), based on a study of several hundred patients in the Netherlands with clinically isolated syndrome.

The ins and outs and pros and cons of the revised McDonald criteria will be discussed in two sessions at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

A highlighted session on Saturday, Oct. 10, at 2:30 p.m. (local time) entitled “Burning Debate: The new McDonald diagnostic criteria are controversial making them difficult to use in clinical practice” aims to shed some light. After an introduction from Emmanuelle Waubant, MD, professor of neurology at the University of California, San Francisco, the topic will be debated by Jiwon Oh, MD, of the University of Toronto and Frauke Zipp, MD, of the University of Mainz (Germany). The experts will take questions from the audience as well as via Twitter. Ask your questions using the meeting hashtag #ECTRIMS2018. Find the session in Hall B.

Five new papers on the impact of the revised criteria will be presented in Hall A on Sunday, Oct. 11, at 8:30 a.m. (local time). Among the investigators presenting are Roos M. van der Vuurst de Vries, MD, from the department of neurology at Erasmus Medical Center in Rotterdam, the Netherlands, who authored the recent JAMA Neurology paper, and Wallace Brownlee, MD, of University College London.

dfulton@mdedge.com

The revised McDonald criteria, issued less than a year ago in December 2017, should allow for earlier diagnosis and treatment of multiple sclerosis, but also could be leading to overdiagnosis and misdiagnosis.

A recent study published in JAMA Neurology found that sensitivity for the 2017 criteria was greater (68% vs. 36% for the 2010 criteria) but specificity was not (61% vs. 85%, respectively), based on a study of several hundred patients in the Netherlands with clinically isolated syndrome.

The ins and outs and pros and cons of the revised McDonald criteria will be discussed in two sessions at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

A highlighted session on Saturday, Oct. 10, at 2:30 p.m. (local time) entitled “Burning Debate: The new McDonald diagnostic criteria are controversial making them difficult to use in clinical practice” aims to shed some light. After an introduction from Emmanuelle Waubant, MD, professor of neurology at the University of California, San Francisco, the topic will be debated by Jiwon Oh, MD, of the University of Toronto and Frauke Zipp, MD, of the University of Mainz (Germany). The experts will take questions from the audience as well as via Twitter. Ask your questions using the meeting hashtag #ECTRIMS2018. Find the session in Hall B.

Five new papers on the impact of the revised criteria will be presented in Hall A on Sunday, Oct. 11, at 8:30 a.m. (local time). Among the investigators presenting are Roos M. van der Vuurst de Vries, MD, from the department of neurology at Erasmus Medical Center in Rotterdam, the Netherlands, who authored the recent JAMA Neurology paper, and Wallace Brownlee, MD, of University College London.

dfulton@mdedge.com

One of the first sessions to begin the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis in Berlin takes a close look at how researchers are honing in on the mechanisms and cellular and molecular mediators that shape the ways in which multiple sclerosis neuropathology differs between individuals.

In the first presentation of the session “Hot Topic 1: Hot topics in MS neuropathology” at 8:00 a.m. (local time) on Oct. 10, Bruce Trapp, PhD, will present the details of the recently published study that he and his associates at the Cleveland Clinic in Ohio conducted on the brains of postmortem MS patients. They describe a new disease subtype, called myelocortical MS, that they characterized through 12 postmortem MS brains in which there was cortical neuronal loss and demyelination of spinal cord and cerebral cortex in the absence of cerebral white matter demyelination.

But what might be driving the degeneration of cerebral gray matter in MS patients, particularly in the cortex? Roberta Magliozzi, PhD, of the University of Verona (Italy), will follow Dr. Trapp’s talk with a presentation of recent neuropathologic findings describing a specific inflammatory protein profile in cerebrospinal fluid (CSF) stemming from meningeal infiltrates and circulating cells in the subarachnoid space that could account for differences in the speed of physical and cognitive disability progression between individuals with MS. Earlier research by Dr. Magliozzi and her colleagues characterized some of these CSF biomarkers. Whether the specific CSF inflammatory pattern proves to be a good surrogate for meningeal inflammation and thereby a good predictor of which MS patients may develop more severe gray matter demyelination and a higher risk of disease progression needs to be examined further.

In the final talk, Claudia Lucchinetti, MD, of the Mayo Clinic, Rochester, Minn., will describe the latest understanding of the pathology of radiologically isolated syndrome.

jevans@mdedge.com

One of the first sessions to begin the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis in Berlin takes a close look at how researchers are honing in on the mechanisms and cellular and molecular mediators that shape the ways in which multiple sclerosis neuropathology differs between individuals.

In the first presentation of the session “Hot Topic 1: Hot topics in MS neuropathology” at 8:00 a.m. (local time) on Oct. 10, Bruce Trapp, PhD, will present the details of the recently published study that he and his associates at the Cleveland Clinic in Ohio conducted on the brains of postmortem MS patients. They describe a new disease subtype, called myelocortical MS, that they characterized through 12 postmortem MS brains in which there was cortical neuronal loss and demyelination of spinal cord and cerebral cortex in the absence of cerebral white matter demyelination.

But what might be driving the degeneration of cerebral gray matter in MS patients, particularly in the cortex? Roberta Magliozzi, PhD, of the University of Verona (Italy), will follow Dr. Trapp’s talk with a presentation of recent neuropathologic findings describing a specific inflammatory protein profile in cerebrospinal fluid (CSF) stemming from meningeal infiltrates and circulating cells in the subarachnoid space that could account for differences in the speed of physical and cognitive disability progression between individuals with MS. Earlier research by Dr. Magliozzi and her colleagues characterized some of these CSF biomarkers. Whether the specific CSF inflammatory pattern proves to be a good surrogate for meningeal inflammation and thereby a good predictor of which MS patients may develop more severe gray matter demyelination and a higher risk of disease progression needs to be examined further.

In the final talk, Claudia Lucchinetti, MD, of the Mayo Clinic, Rochester, Minn., will describe the latest understanding of the pathology of radiologically isolated syndrome.

jevans@mdedge.com

One of the first sessions to begin the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis in Berlin takes a close look at how researchers are honing in on the mechanisms and cellular and molecular mediators that shape the ways in which multiple sclerosis neuropathology differs between individuals.

In the first presentation of the session “Hot Topic 1: Hot topics in MS neuropathology” at 8:00 a.m. (local time) on Oct. 10, Bruce Trapp, PhD, will present the details of the recently published study that he and his associates at the Cleveland Clinic in Ohio conducted on the brains of postmortem MS patients. They describe a new disease subtype, called myelocortical MS, that they characterized through 12 postmortem MS brains in which there was cortical neuronal loss and demyelination of spinal cord and cerebral cortex in the absence of cerebral white matter demyelination.

But what might be driving the degeneration of cerebral gray matter in MS patients, particularly in the cortex? Roberta Magliozzi, PhD, of the University of Verona (Italy), will follow Dr. Trapp’s talk with a presentation of recent neuropathologic findings describing a specific inflammatory protein profile in cerebrospinal fluid (CSF) stemming from meningeal infiltrates and circulating cells in the subarachnoid space that could account for differences in the speed of physical and cognitive disability progression between individuals with MS. Earlier research by Dr. Magliozzi and her colleagues characterized some of these CSF biomarkers. Whether the specific CSF inflammatory pattern proves to be a good surrogate for meningeal inflammation and thereby a good predictor of which MS patients may develop more severe gray matter demyelination and a higher risk of disease progression needs to be examined further.

In the final talk, Claudia Lucchinetti, MD, of the Mayo Clinic, Rochester, Minn., will describe the latest understanding of the pathology of radiologically isolated syndrome.

jevans@mdedge.com

A new subtype of multiple sclerosis (MS) called myelocortical MS is characterized by demyelination only in the spinal cord and cerebral cortex and not in the cerebral white matter, according to a study published online ahead of print August 21 in Lancet Neurology. The findings are based on an examination of the brains and spinal cords of 100 patients who died of MS.

Bruce D. Trapp, PhD, the Morris R. and Ruth V. Graham Endowed Chair in Biomedical Research at the Lerner Research Institute at the Cleveland Clinic in Ohio, and his coauthors said that while the demyelination of cerebral white matter is a pathologic hallmark of MS, previous research has found that only around half of cerebral T2-weighted hyperintense white matter lesions are demyelinated, and these lesions account for less than a third of variance in the rate of brain atrophy.

“In the absence of specific MRI metrics for demyelination, the relationship between cerebral white-matter demyelination and neurodegeneration remains speculative,” they said.

Not Typical MS

They found that while individuals with myelocortical MS did not have demyelinated lesions in the cerebral white matter, they had areas of demyelinated lesions in the cerebral cortex similar to those of individuals with typical MS (median 4.45% vs 9.74%, respectively). However, the individuals with myelocortical MS had a significantly smaller area of spinal cord demyelination (median 3.81% vs 13.81%).

Individuals with myelocortical MS also had significantly lower mean cortical neuronal densities, compared with healthy control brains, in layer III, layer V, and layer VI. But individuals with typical MS only had a lower cortical neuronal density in layer V when compared with controls.

Dr. Trapp and colleagues also saw that in typical MS, neuronal density decreased as the area of brain white-matter demyelination increased. However, this negative linear correlation was not seen in myelocortical MS.

On MRI, researchers were still able to see abnormalities in the cerebral white matter in individuals with myelocortical MS, in T2-weighted, T1-weighted, and magnetization transfer ratios (MTR) images. They also found similar total T2-weighted and T1-weighted lesion volumes in individuals with myelocortical MS and those with typical MS, although individuals with typical MS had significantly greater MTR lesion volumes.

The Hallmarks of Myelocortical MS

“We propose that myelocortical MS is characterized by spinal cord demyelination, subpial cortical demyelination, and an absence of cerebral white-matter demyelination,” Dr. Trapp and colleagues wrote. “Our findings indicate that abnormal cerebral white-matter T2-T1-MTR regions of interest are not always demyelinated, and this pathologic evidence suggests that cerebral white-matter demyelination and cortical neuronal degeneration can be independent events in myelocortical MS.”

The authors acknowledged that one limitation of their study may have been selection bias, as all the patients in the study died from complications of advanced MS. They suggested that it was therefore not appropriate to conclude that the prevalence of myelocortical MS seen in their sample would be similar across the entire MS population, nor were the findings likely to apply to pateints with earlier stage disease.

The study received funding from the NIH and the National MS Society. One author is an employee of Renovo Neural, and three authors are employees of Biogen. One author declared a pending patent related to automated lesion segmentation from MRI images, and four authors declared funding, fees, and nonfinancial support from pharmaceutical companies.

—Bianca Nogrady

Suggested Reading

Trapp BD, Vignos M, Dudman J, et al. Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Lancet Neurol. 2018 Aug 21 [Epub ahead of print].

A new subtype of multiple sclerosis (MS) called myelocortical MS is characterized by demyelination only in the spinal cord and cerebral cortex and not in the cerebral white matter, according to a study published online ahead of print August 21 in Lancet Neurology. The findings are based on an examination of the brains and spinal cords of 100 patients who died of MS.

Bruce D. Trapp, PhD, the Morris R. and Ruth V. Graham Endowed Chair in Biomedical Research at the Lerner Research Institute at the Cleveland Clinic in Ohio, and his coauthors said that while the demyelination of cerebral white matter is a pathologic hallmark of MS, previous research has found that only around half of cerebral T2-weighted hyperintense white matter lesions are demyelinated, and these lesions account for less than a third of variance in the rate of brain atrophy.

“In the absence of specific MRI metrics for demyelination, the relationship between cerebral white-matter demyelination and neurodegeneration remains speculative,” they said.

Not Typical MS

They found that while individuals with myelocortical MS did not have demyelinated lesions in the cerebral white matter, they had areas of demyelinated lesions in the cerebral cortex similar to those of individuals with typical MS (median 4.45% vs 9.74%, respectively). However, the individuals with myelocortical MS had a significantly smaller area of spinal cord demyelination (median 3.81% vs 13.81%).

Individuals with myelocortical MS also had significantly lower mean cortical neuronal densities, compared with healthy control brains, in layer III, layer V, and layer VI. But individuals with typical MS only had a lower cortical neuronal density in layer V when compared with controls.

Dr. Trapp and colleagues also saw that in typical MS, neuronal density decreased as the area of brain white-matter demyelination increased. However, this negative linear correlation was not seen in myelocortical MS.

On MRI, researchers were still able to see abnormalities in the cerebral white matter in individuals with myelocortical MS, in T2-weighted, T1-weighted, and magnetization transfer ratios (MTR) images. They also found similar total T2-weighted and T1-weighted lesion volumes in individuals with myelocortical MS and those with typical MS, although individuals with typical MS had significantly greater MTR lesion volumes.

The Hallmarks of Myelocortical MS

“We propose that myelocortical MS is characterized by spinal cord demyelination, subpial cortical demyelination, and an absence of cerebral white-matter demyelination,” Dr. Trapp and colleagues wrote. “Our findings indicate that abnormal cerebral white-matter T2-T1-MTR regions of interest are not always demyelinated, and this pathologic evidence suggests that cerebral white-matter demyelination and cortical neuronal degeneration can be independent events in myelocortical MS.”

The authors acknowledged that one limitation of their study may have been selection bias, as all the patients in the study died from complications of advanced MS. They suggested that it was therefore not appropriate to conclude that the prevalence of myelocortical MS seen in their sample would be similar across the entire MS population, nor were the findings likely to apply to pateints with earlier stage disease.

The study received funding from the NIH and the National MS Society. One author is an employee of Renovo Neural, and three authors are employees of Biogen. One author declared a pending patent related to automated lesion segmentation from MRI images, and four authors declared funding, fees, and nonfinancial support from pharmaceutical companies.

—Bianca Nogrady

Suggested Reading

Trapp BD, Vignos M, Dudman J, et al. Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Lancet Neurol. 2018 Aug 21 [Epub ahead of print].

A new subtype of multiple sclerosis (MS) called myelocortical MS is characterized by demyelination only in the spinal cord and cerebral cortex and not in the cerebral white matter, according to a study published online ahead of print August 21 in Lancet Neurology. The findings are based on an examination of the brains and spinal cords of 100 patients who died of MS.

Bruce D. Trapp, PhD, the Morris R. and Ruth V. Graham Endowed Chair in Biomedical Research at the Lerner Research Institute at the Cleveland Clinic in Ohio, and his coauthors said that while the demyelination of cerebral white matter is a pathologic hallmark of MS, previous research has found that only around half of cerebral T2-weighted hyperintense white matter lesions are demyelinated, and these lesions account for less than a third of variance in the rate of brain atrophy.

“In the absence of specific MRI metrics for demyelination, the relationship between cerebral white-matter demyelination and neurodegeneration remains speculative,” they said.

Not Typical MS

They found that while individuals with myelocortical MS did not have demyelinated lesions in the cerebral white matter, they had areas of demyelinated lesions in the cerebral cortex similar to those of individuals with typical MS (median 4.45% vs 9.74%, respectively). However, the individuals with myelocortical MS had a significantly smaller area of spinal cord demyelination (median 3.81% vs 13.81%).

Individuals with myelocortical MS also had significantly lower mean cortical neuronal densities, compared with healthy control brains, in layer III, layer V, and layer VI. But individuals with typical MS only had a lower cortical neuronal density in layer V when compared with controls.

Dr. Trapp and colleagues also saw that in typical MS, neuronal density decreased as the area of brain white-matter demyelination increased. However, this negative linear correlation was not seen in myelocortical MS.

On MRI, researchers were still able to see abnormalities in the cerebral white matter in individuals with myelocortical MS, in T2-weighted, T1-weighted, and magnetization transfer ratios (MTR) images. They also found similar total T2-weighted and T1-weighted lesion volumes in individuals with myelocortical MS and those with typical MS, although individuals with typical MS had significantly greater MTR lesion volumes.

The Hallmarks of Myelocortical MS

“We propose that myelocortical MS is characterized by spinal cord demyelination, subpial cortical demyelination, and an absence of cerebral white-matter demyelination,” Dr. Trapp and colleagues wrote. “Our findings indicate that abnormal cerebral white-matter T2-T1-MTR regions of interest are not always demyelinated, and this pathologic evidence suggests that cerebral white-matter demyelination and cortical neuronal degeneration can be independent events in myelocortical MS.”

The authors acknowledged that one limitation of their study may have been selection bias, as all the patients in the study died from complications of advanced MS. They suggested that it was therefore not appropriate to conclude that the prevalence of myelocortical MS seen in their sample would be similar across the entire MS population, nor were the findings likely to apply to pateints with earlier stage disease.

The study received funding from the NIH and the National MS Society. One author is an employee of Renovo Neural, and three authors are employees of Biogen. One author declared a pending patent related to automated lesion segmentation from MRI images, and four authors declared funding, fees, and nonfinancial support from pharmaceutical companies.

—Bianca Nogrady

Suggested Reading

Trapp BD, Vignos M, Dudman J, et al. Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Lancet Neurol. 2018 Aug 21 [Epub ahead of print].

HILTON HEAD, SC—Given the lack of a definitive diagnostic test for multiple sclerosis (MS), diagnosing the disease can prove difficult. When considering symptoms, signs, and MRI findings that are suggestive of MS, clinicians must rely on their clinical judgment and experience, skillful interpretation of tests, and knowledge of and willingness to consider alternative diagnoses. Because of the subjective judgments involved and the many conditions that may mimic MS, it is not surprising that physicians sometimes misdiagnose MS, said Harold Moses, MD, at Vanderbilt University’s 41st Annual Contemporary Clinical Neurology Symposium.

A study by Solomon et al suggests ways to reduce the likelihood of misdiagnosis, said Dr. Moses, Associate Professor of Neurology at Vanderbilt University in Nashville. “Neurologists should … avoid overreliance on MRI changes as the principal support for an MS diagnosis,” he said. “Nonspecific or atypical MRI findings should be interpreted cautiously. A diagnosis of MS should not be made or reinforced in patients with psychiatric conditions without evidence for MS.”

For patients with emotional distress and psychologically based functional disability who do not meet diagnostic criteria for MS, a diagnosis of MS should be avoided. When MS remains a possibility, the patient should be informed of that fact and followed with clinical assessment and, if appropriate, MRI, Dr. Moses added. “Neurologists should be open in admitting and discussing uncertainty with patients,” he said. “It’s important to be honest in … indicating the need for further testing or observation over time. When emotional factors are thought to contribute [to a patient’s symptoms], treatments should be directed at these issues concurrently.”

First, Do No Harm

Psychiatrists and other therapists may be able to help patients when the diagnosis remains an open question. “MS disease-modifying drugs should be prescribed only for patients who have definitive evidence for MS or for those who present with classical clinically isolated syndromes—optic neuritis, transverse myelitis, and brainstem events—accompanied by appropriate changes on MRI,” Dr. Moses said.

Challenging cases include asymptomatic patients with MRI findings; patients with a first occurrence of symptoms, especially when the presentation is atypical; and patients with mimics of MS, such as vasculitis. Neurologists should be vigilant to identify mimics, particularly because these conditions may be treatable. The presence of psychiatric illness also may create challenging clinical scenarios.

“Psychologic and psychiatric factors may be present, but that patient may still have MS…. The question is, how do you tease out why that person is not doing well—that discordance, if you will, between how their MRI and exam are versus how they feel and how they are functioning.”

A Survey of Specialists

Solomon et al conducted a cross-sectional, internet-based survey of 242 MS specialists. Of the 50.4% of physicians who responded, 95% reported evaluating within the past year at least one patient who had been diagnosed with MS but who they felt strongly did not have the disease. More than 90% of respondents reported the use of disease-modifying therapy (DMT) in a proportion of these patients, and 94% found clinical encounters with these patients to be of an equal or greater challenge than making a new diagnosis of MS. A smaller proportion of respondents (14%) reported that, in some cases, they withheld telling a patient their opinion that the patient did not have MS.

As the study’s authors observed, evidence of therapeutic benefit from early initiation of DMT in patients with MS generates a sense of urgency to diagnose the disease early and begin therapy, Dr. Moses said. However, misdiagnosis in many cases may have resulted from—in place of prudent clinical and laboratory monitoring—an overreliance on MRI findings in patients with syndromes for which established MS diagnostic imaging criteria have not been validated. “Ultimately, MS remains a clinical diagnosis,” said Dr. Moses. “You use an MRI as an adjunct to help you confirm a diagnosis.”

Misdiagnosis of MS can cause serious harm. For example, conditions such as neuromyelitis optica and cervical spondylosis can lead to irreversible disability if unrecognized and inappropriately treated. Use of DMT in patients without MS exposes them to unnecessary health risks and financial costs. Dr. Moses cited the case of a 45-year-old woman who probably did not have MS but whose treatment with interferon beta-1a likely resulted in her going on dialysis. “These drugs are not benign,” he said. “[Such an outcome] is a very rare thing, but keep in mind that if a patient does not have MS, he or she should not be on MS therapy.”

Invested in the Diagnosis

As discussed by Boissy and Ford, neurologists may be inclined to use a medically inaccurate label, such as “a touch of MS,” “mild MS,” “benign MS,” or “MS by history,” when talking with patients who have received a misdiagnosis of MS, Dr. Moses said. Patients who have attributed psychogenic symptoms to misdiagnosed MS often resist a psychogenic explanation. In addition, they may be invested physically, emotionally, and financially in the diagnosis of MS—making treatment challenging for clinicians, Dr. Moses said.

Therapeutic mislabeling raises ethical issues, however. Mislabeling may expose patients to risky therapies, lead to an inappropriate use of resources, compromise the credibility of the clinician, and cause psychologic harm to the patient.

Neurologists would do better to consider scheduling multiple visits to explore psychogenic factors, as well as the patient’s fears and emotions, with the aim of developing a rapport and encouraging appropriate evaluations, Dr. Moses said. “If physicians endorse an inaccurate diagnosis, this undoubtedly conflicts with their professional obligations for truth telling, avoiding harming patients, … acting in the patient’s best interest, and stewardship of medical resources,” he said.

—Fred Balzac

Suggested Reading

Boissy AR, Ford PJ. A touch of MS: therapeutic mislabeling. Neurology. 2012;78(24):1981-1985.

Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology. 2016;87(13):1393-1399.

Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.

HILTON HEAD, SC—Given the lack of a definitive diagnostic test for multiple sclerosis (MS), diagnosing the disease can prove difficult. When considering symptoms, signs, and MRI findings that are suggestive of MS, clinicians must rely on their clinical judgment and experience, skillful interpretation of tests, and knowledge of and willingness to consider alternative diagnoses. Because of the subjective judgments involved and the many conditions that may mimic MS, it is not surprising that physicians sometimes misdiagnose MS, said Harold Moses, MD, at Vanderbilt University’s 41st Annual Contemporary Clinical Neurology Symposium.

A study by Solomon et al suggests ways to reduce the likelihood of misdiagnosis, said Dr. Moses, Associate Professor of Neurology at Vanderbilt University in Nashville. “Neurologists should … avoid overreliance on MRI changes as the principal support for an MS diagnosis,” he said. “Nonspecific or atypical MRI findings should be interpreted cautiously. A diagnosis of MS should not be made or reinforced in patients with psychiatric conditions without evidence for MS.”

For patients with emotional distress and psychologically based functional disability who do not meet diagnostic criteria for MS, a diagnosis of MS should be avoided. When MS remains a possibility, the patient should be informed of that fact and followed with clinical assessment and, if appropriate, MRI, Dr. Moses added. “Neurologists should be open in admitting and discussing uncertainty with patients,” he said. “It’s important to be honest in … indicating the need for further testing or observation over time. When emotional factors are thought to contribute [to a patient’s symptoms], treatments should be directed at these issues concurrently.”

First, Do No Harm

Psychiatrists and other therapists may be able to help patients when the diagnosis remains an open question. “MS disease-modifying drugs should be prescribed only for patients who have definitive evidence for MS or for those who present with classical clinically isolated syndromes—optic neuritis, transverse myelitis, and brainstem events—accompanied by appropriate changes on MRI,” Dr. Moses said.

Challenging cases include asymptomatic patients with MRI findings; patients with a first occurrence of symptoms, especially when the presentation is atypical; and patients with mimics of MS, such as vasculitis. Neurologists should be vigilant to identify mimics, particularly because these conditions may be treatable. The presence of psychiatric illness also may create challenging clinical scenarios.

“Psychologic and psychiatric factors may be present, but that patient may still have MS…. The question is, how do you tease out why that person is not doing well—that discordance, if you will, between how their MRI and exam are versus how they feel and how they are functioning.”

A Survey of Specialists

Solomon et al conducted a cross-sectional, internet-based survey of 242 MS specialists. Of the 50.4% of physicians who responded, 95% reported evaluating within the past year at least one patient who had been diagnosed with MS but who they felt strongly did not have the disease. More than 90% of respondents reported the use of disease-modifying therapy (DMT) in a proportion of these patients, and 94% found clinical encounters with these patients to be of an equal or greater challenge than making a new diagnosis of MS. A smaller proportion of respondents (14%) reported that, in some cases, they withheld telling a patient their opinion that the patient did not have MS.

As the study’s authors observed, evidence of therapeutic benefit from early initiation of DMT in patients with MS generates a sense of urgency to diagnose the disease early and begin therapy, Dr. Moses said. However, misdiagnosis in many cases may have resulted from—in place of prudent clinical and laboratory monitoring—an overreliance on MRI findings in patients with syndromes for which established MS diagnostic imaging criteria have not been validated. “Ultimately, MS remains a clinical diagnosis,” said Dr. Moses. “You use an MRI as an adjunct to help you confirm a diagnosis.”

Misdiagnosis of MS can cause serious harm. For example, conditions such as neuromyelitis optica and cervical spondylosis can lead to irreversible disability if unrecognized and inappropriately treated. Use of DMT in patients without MS exposes them to unnecessary health risks and financial costs. Dr. Moses cited the case of a 45-year-old woman who probably did not have MS but whose treatment with interferon beta-1a likely resulted in her going on dialysis. “These drugs are not benign,” he said. “[Such an outcome] is a very rare thing, but keep in mind that if a patient does not have MS, he or she should not be on MS therapy.”

Invested in the Diagnosis

As discussed by Boissy and Ford, neurologists may be inclined to use a medically inaccurate label, such as “a touch of MS,” “mild MS,” “benign MS,” or “MS by history,” when talking with patients who have received a misdiagnosis of MS, Dr. Moses said. Patients who have attributed psychogenic symptoms to misdiagnosed MS often resist a psychogenic explanation. In addition, they may be invested physically, emotionally, and financially in the diagnosis of MS—making treatment challenging for clinicians, Dr. Moses said.

Therapeutic mislabeling raises ethical issues, however. Mislabeling may expose patients to risky therapies, lead to an inappropriate use of resources, compromise the credibility of the clinician, and cause psychologic harm to the patient.

Neurologists would do better to consider scheduling multiple visits to explore psychogenic factors, as well as the patient’s fears and emotions, with the aim of developing a rapport and encouraging appropriate evaluations, Dr. Moses said. “If physicians endorse an inaccurate diagnosis, this undoubtedly conflicts with their professional obligations for truth telling, avoiding harming patients, … acting in the patient’s best interest, and stewardship of medical resources,” he said.

—Fred Balzac

Suggested Reading

Boissy AR, Ford PJ. A touch of MS: therapeutic mislabeling. Neurology. 2012;78(24):1981-1985.

Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology. 2016;87(13):1393-1399.

Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.

HILTON HEAD, SC—Given the lack of a definitive diagnostic test for multiple sclerosis (MS), diagnosing the disease can prove difficult. When considering symptoms, signs, and MRI findings that are suggestive of MS, clinicians must rely on their clinical judgment and experience, skillful interpretation of tests, and knowledge of and willingness to consider alternative diagnoses. Because of the subjective judgments involved and the many conditions that may mimic MS, it is not surprising that physicians sometimes misdiagnose MS, said Harold Moses, MD, at Vanderbilt University’s 41st Annual Contemporary Clinical Neurology Symposium.

A study by Solomon et al suggests ways to reduce the likelihood of misdiagnosis, said Dr. Moses, Associate Professor of Neurology at Vanderbilt University in Nashville. “Neurologists should … avoid overreliance on MRI changes as the principal support for an MS diagnosis,” he said. “Nonspecific or atypical MRI findings should be interpreted cautiously. A diagnosis of MS should not be made or reinforced in patients with psychiatric conditions without evidence for MS.”

For patients with emotional distress and psychologically based functional disability who do not meet diagnostic criteria for MS, a diagnosis of MS should be avoided. When MS remains a possibility, the patient should be informed of that fact and followed with clinical assessment and, if appropriate, MRI, Dr. Moses added. “Neurologists should be open in admitting and discussing uncertainty with patients,” he said. “It’s important to be honest in … indicating the need for further testing or observation over time. When emotional factors are thought to contribute [to a patient’s symptoms], treatments should be directed at these issues concurrently.”

First, Do No Harm

Psychiatrists and other therapists may be able to help patients when the diagnosis remains an open question. “MS disease-modifying drugs should be prescribed only for patients who have definitive evidence for MS or for those who present with classical clinically isolated syndromes—optic neuritis, transverse myelitis, and brainstem events—accompanied by appropriate changes on MRI,” Dr. Moses said.

Challenging cases include asymptomatic patients with MRI findings; patients with a first occurrence of symptoms, especially when the presentation is atypical; and patients with mimics of MS, such as vasculitis. Neurologists should be vigilant to identify mimics, particularly because these conditions may be treatable. The presence of psychiatric illness also may create challenging clinical scenarios.

“Psychologic and psychiatric factors may be present, but that patient may still have MS…. The question is, how do you tease out why that person is not doing well—that discordance, if you will, between how their MRI and exam are versus how they feel and how they are functioning.”

A Survey of Specialists

Solomon et al conducted a cross-sectional, internet-based survey of 242 MS specialists. Of the 50.4% of physicians who responded, 95% reported evaluating within the past year at least one patient who had been diagnosed with MS but who they felt strongly did not have the disease. More than 90% of respondents reported the use of disease-modifying therapy (DMT) in a proportion of these patients, and 94% found clinical encounters with these patients to be of an equal or greater challenge than making a new diagnosis of MS. A smaller proportion of respondents (14%) reported that, in some cases, they withheld telling a patient their opinion that the patient did not have MS.

As the study’s authors observed, evidence of therapeutic benefit from early initiation of DMT in patients with MS generates a sense of urgency to diagnose the disease early and begin therapy, Dr. Moses said. However, misdiagnosis in many cases may have resulted from—in place of prudent clinical and laboratory monitoring—an overreliance on MRI findings in patients with syndromes for which established MS diagnostic imaging criteria have not been validated. “Ultimately, MS remains a clinical diagnosis,” said Dr. Moses. “You use an MRI as an adjunct to help you confirm a diagnosis.”

Misdiagnosis of MS can cause serious harm. For example, conditions such as neuromyelitis optica and cervical spondylosis can lead to irreversible disability if unrecognized and inappropriately treated. Use of DMT in patients without MS exposes them to unnecessary health risks and financial costs. Dr. Moses cited the case of a 45-year-old woman who probably did not have MS but whose treatment with interferon beta-1a likely resulted in her going on dialysis. “These drugs are not benign,” he said. “[Such an outcome] is a very rare thing, but keep in mind that if a patient does not have MS, he or she should not be on MS therapy.”

Invested in the Diagnosis

As discussed by Boissy and Ford, neurologists may be inclined to use a medically inaccurate label, such as “a touch of MS,” “mild MS,” “benign MS,” or “MS by history,” when talking with patients who have received a misdiagnosis of MS, Dr. Moses said. Patients who have attributed psychogenic symptoms to misdiagnosed MS often resist a psychogenic explanation. In addition, they may be invested physically, emotionally, and financially in the diagnosis of MS—making treatment challenging for clinicians, Dr. Moses said.

Therapeutic mislabeling raises ethical issues, however. Mislabeling may expose patients to risky therapies, lead to an inappropriate use of resources, compromise the credibility of the clinician, and cause psychologic harm to the patient.

Neurologists would do better to consider scheduling multiple visits to explore psychogenic factors, as well as the patient’s fears and emotions, with the aim of developing a rapport and encouraging appropriate evaluations, Dr. Moses said. “If physicians endorse an inaccurate diagnosis, this undoubtedly conflicts with their professional obligations for truth telling, avoiding harming patients, … acting in the patient’s best interest, and stewardship of medical resources,” he said.

—Fred Balzac

Suggested Reading

Boissy AR, Ford PJ. A touch of MS: therapeutic mislabeling. Neurology. 2012;78(24):1981-1985.

Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology. 2016;87(13):1393-1399.

Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.

BALTIMORE—Objective and subjective sleep measures are associated with fatigue in people with multiple sclerosis (MS), according to a meta-analysis presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

Evidence suggests that individuals with MS have disruptions in sleep that are associated with and may contribute to fatigue, said Jagriti “Jackie” Bhattarai, PhD, a postdoctoral fellow in the MS Rehabilitation Research Laboratory at the Johns Hopkins School of Medicine’s Department of Physical Medicine and Rehabilitation in Baltimore. Among the sleep parameters investigated, sleep staging, sleep-related movement, and subjective insomnia had moderate associations with fatigue. Other sleep parameters examined in the study were not statistically significantly associated with fatigue, she said.

A Major Factor in Disability

Fatigue is a leading contributor to disability in patients with MS. Although fatigue is a complex symptom with multiple neurologic and behavioral causes, emerging evidence suggests that “sleep disturbance may have a significant role in the development or maintenance of fatigue in MS,” Dr. Bhattarai said. The relationship between sleep parameters and fatigue in people with MS is not well understood, however, she said.

To examine the relationship between commonly used sleep parameters and fatigue in MS, Dr. Bhattarai and colleagues identified studies that included at least one validated measure of fatigue and one validated measure of sleep disturbance. They included studies that reported the effect sizes of the associations between sleep and fatigue or provided enough data for the investigators to compute the effect sizes.

Their meta-analysis included 37 studies with 6,129 participants. Participants had an average age of 42 and MS duration of 9.5 years. About 80% of the sample had relapsing-remitting MS.

Sleep measures included polysomnography, actigraphy, and the multiple sleep latency test, as well as subjective measures such as the Insomnia Severity Index, the Pittsburgh Sleep Quality Index, and the Medical Outcomes Study Sleep Scale.

Fatigue was measured using the Fatigue Severity Scale, the modified Fatigue Impact Scale, or the Neurological Fatigue Index for MS.

Effect sizes varied across studies, as did the parameters examined within each study. The mean effect size was the largest for the association between REM sleep onset latency (ie, the time between sleep onset and initiation of REM sleep) and fatigue (r = 0.42), though this effect size was based on only two studies, and the association requires further investigation. “Shorter REM sleep onset latency has been associated with depression and narcolepsy,” both of which are more common in people with MS than in the general population, Dr. Bhattarai said. Subjective insomnia (r = 0.36) and objective sleep-related movement (r = 0.34) also yielded moderate effect sizes. “The shorter the REM sleep onset latency and the more subjective complaints that individuals have about their sleep, the greater the level of fatigue people with MS reported,” she said. “The more sleep-related movement that people have, the greater their level of MS-related fatigue.”

Potential to Inform Treatment Approach

The association between fatigue and objective sleep-disordered breathing was not statistically significant. Subjective sleep-disordered breathing, objective nocturnal arousals, sleep efficiency, sleep onset latency, and sleep duration had weak effect sizes. These problems are common and require treatment, however, Dr. Bhattarai said.

“When treating patients with MS who are experiencing MS-related fatigue, interventions geared toward improving patients’ perceived sleep quality and addressing MS symptoms that might disrupt sleep (eg, nocturia and periodic leg movements) may offer an avenue for improving fatigue,” said Dr. Bhattarai. “However, these effects remain to be shown in a randomized controlled trial.”

—Jake Remaly

BALTIMORE—Objective and subjective sleep measures are associated with fatigue in people with multiple sclerosis (MS), according to a meta-analysis presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

Evidence suggests that individuals with MS have disruptions in sleep that are associated with and may contribute to fatigue, said Jagriti “Jackie” Bhattarai, PhD, a postdoctoral fellow in the MS Rehabilitation Research Laboratory at the Johns Hopkins School of Medicine’s Department of Physical Medicine and Rehabilitation in Baltimore. Among the sleep parameters investigated, sleep staging, sleep-related movement, and subjective insomnia had moderate associations with fatigue. Other sleep parameters examined in the study were not statistically significantly associated with fatigue, she said.

A Major Factor in Disability

Fatigue is a leading contributor to disability in patients with MS. Although fatigue is a complex symptom with multiple neurologic and behavioral causes, emerging evidence suggests that “sleep disturbance may have a significant role in the development or maintenance of fatigue in MS,” Dr. Bhattarai said. The relationship between sleep parameters and fatigue in people with MS is not well understood, however, she said.

To examine the relationship between commonly used sleep parameters and fatigue in MS, Dr. Bhattarai and colleagues identified studies that included at least one validated measure of fatigue and one validated measure of sleep disturbance. They included studies that reported the effect sizes of the associations between sleep and fatigue or provided enough data for the investigators to compute the effect sizes.

Their meta-analysis included 37 studies with 6,129 participants. Participants had an average age of 42 and MS duration of 9.5 years. About 80% of the sample had relapsing-remitting MS.

Sleep measures included polysomnography, actigraphy, and the multiple sleep latency test, as well as subjective measures such as the Insomnia Severity Index, the Pittsburgh Sleep Quality Index, and the Medical Outcomes Study Sleep Scale.

Fatigue was measured using the Fatigue Severity Scale, the modified Fatigue Impact Scale, or the Neurological Fatigue Index for MS.

Effect sizes varied across studies, as did the parameters examined within each study. The mean effect size was the largest for the association between REM sleep onset latency (ie, the time between sleep onset and initiation of REM sleep) and fatigue (r = 0.42), though this effect size was based on only two studies, and the association requires further investigation. “Shorter REM sleep onset latency has been associated with depression and narcolepsy,” both of which are more common in people with MS than in the general population, Dr. Bhattarai said. Subjective insomnia (r = 0.36) and objective sleep-related movement (r = 0.34) also yielded moderate effect sizes. “The shorter the REM sleep onset latency and the more subjective complaints that individuals have about their sleep, the greater the level of fatigue people with MS reported,” she said. “The more sleep-related movement that people have, the greater their level of MS-related fatigue.”

Potential to Inform Treatment Approach

The association between fatigue and objective sleep-disordered breathing was not statistically significant. Subjective sleep-disordered breathing, objective nocturnal arousals, sleep efficiency, sleep onset latency, and sleep duration had weak effect sizes. These problems are common and require treatment, however, Dr. Bhattarai said.

“When treating patients with MS who are experiencing MS-related fatigue, interventions geared toward improving patients’ perceived sleep quality and addressing MS symptoms that might disrupt sleep (eg, nocturia and periodic leg movements) may offer an avenue for improving fatigue,” said Dr. Bhattarai. “However, these effects remain to be shown in a randomized controlled trial.”

—Jake Remaly

BALTIMORE—Objective and subjective sleep measures are associated with fatigue in people with multiple sclerosis (MS), according to a meta-analysis presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

Evidence suggests that individuals with MS have disruptions in sleep that are associated with and may contribute to fatigue, said Jagriti “Jackie” Bhattarai, PhD, a postdoctoral fellow in the MS Rehabilitation Research Laboratory at the Johns Hopkins School of Medicine’s Department of Physical Medicine and Rehabilitation in Baltimore. Among the sleep parameters investigated, sleep staging, sleep-related movement, and subjective insomnia had moderate associations with fatigue. Other sleep parameters examined in the study were not statistically significantly associated with fatigue, she said.

A Major Factor in Disability

Fatigue is a leading contributor to disability in patients with MS. Although fatigue is a complex symptom with multiple neurologic and behavioral causes, emerging evidence suggests that “sleep disturbance may have a significant role in the development or maintenance of fatigue in MS,” Dr. Bhattarai said. The relationship between sleep parameters and fatigue in people with MS is not well understood, however, she said.

To examine the relationship between commonly used sleep parameters and fatigue in MS, Dr. Bhattarai and colleagues identified studies that included at least one validated measure of fatigue and one validated measure of sleep disturbance. They included studies that reported the effect sizes of the associations between sleep and fatigue or provided enough data for the investigators to compute the effect sizes.

Their meta-analysis included 37 studies with 6,129 participants. Participants had an average age of 42 and MS duration of 9.5 years. About 80% of the sample had relapsing-remitting MS.

Sleep measures included polysomnography, actigraphy, and the multiple sleep latency test, as well as subjective measures such as the Insomnia Severity Index, the Pittsburgh Sleep Quality Index, and the Medical Outcomes Study Sleep Scale.

Fatigue was measured using the Fatigue Severity Scale, the modified Fatigue Impact Scale, or the Neurological Fatigue Index for MS.

Effect sizes varied across studies, as did the parameters examined within each study. The mean effect size was the largest for the association between REM sleep onset latency (ie, the time between sleep onset and initiation of REM sleep) and fatigue (r = 0.42), though this effect size was based on only two studies, and the association requires further investigation. “Shorter REM sleep onset latency has been associated with depression and narcolepsy,” both of which are more common in people with MS than in the general population, Dr. Bhattarai said. Subjective insomnia (r = 0.36) and objective sleep-related movement (r = 0.34) also yielded moderate effect sizes. “The shorter the REM sleep onset latency and the more subjective complaints that individuals have about their sleep, the greater the level of fatigue people with MS reported,” she said. “The more sleep-related movement that people have, the greater their level of MS-related fatigue.”

Potential to Inform Treatment Approach

The association between fatigue and objective sleep-disordered breathing was not statistically significant. Subjective sleep-disordered breathing, objective nocturnal arousals, sleep efficiency, sleep onset latency, and sleep duration had weak effect sizes. These problems are common and require treatment, however, Dr. Bhattarai said.

“When treating patients with MS who are experiencing MS-related fatigue, interventions geared toward improving patients’ perceived sleep quality and addressing MS symptoms that might disrupt sleep (eg, nocturia and periodic leg movements) may offer an avenue for improving fatigue,” said Dr. Bhattarai. “However, these effects remain to be shown in a randomized controlled trial.”

—Jake Remaly