Multiple Sclerosis Hub

BERLIN – In addition to the pain, motor and sensory impairments, and cognitive dysfunction that can stalk multiple sclerosis (MS) patients, for many, there’s also the challenge of an invisible, tough-to-quantify entity: fatigue.

©RusN/Thinkstock.com

“Approximately 80% of patients suffer from fatigue, so it’s an immense problem in MS. There’s no real clear relationship with disease severity,” Vincent de Groot, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “Despite what a lot of people think, there’s no clear or strong relationship between fatigue and the amount of physical activity people undertake daily,” he noted.

“Patients all know what we are talking about when we ask about fatigue,” but there are a variety of definitions of fatigue used in research, a fact that has limited progress in the field, said Dr. de Groot.

Primary fatigue is related to the pathophysiology of MS itself, while secondary fatigue can result from MS symptoms, such as poor sleep from spasms. Secondary fatigue can also be a side effect of MS medications; baclofen, used for spasticity, is a good example, said Dr. de Groot. “We must not underestimate how many problems these drugs can give people.”

What’s the mechanism by which MS causes primary fatigue? “The simple answer is that we do not know,” said Dr. de Groot, a physiatrist and researcher at Vrije University, Amsterdam.

Though immune-mediated fatigue had been proposed as a factor for patients with MS, Dr. de Groot said that his own lab’s work has not found any connection between fatigue levels and any immune-related biomarkers. “So I don’t think the immune hypothesis has a lot of evidence.”

Similarly, though there might be mechanistic reasons to suspect the hypothalamic-pituitary-adrenal (HPA) axis as a culprit for MS fatigue, no consistent association has been found between any markers for HPA axis disruption and fatigue ratings, Dr. de Groot said.

Newer theories center on MS-related disruptions in brain connectivity, with imaging studies now able to detect some of these disruptions in functional connectivity that correlate with fatigue. “Right now, I think this is the hypothesis to bet money on,” Dr. de Groot said.

Many factors come into play, including environmental and psychological factors, he said.

“What can we do to treat MS-related fatigue?” Though several drugs have been used, “if you carefully look at the systematic reviews, the evidence is very, very disappointing,” Dr. de Groot said. For both amantadine and modafinil, “there is no evidence that these drugs are effective,” he said, citing a systematic review and meta-analysis that found a pooled effect size of 0.07 (95% confidence interval, –0.22 to 0.37) for medications (Mult Scler Int. 2014 May; doi: 10.1155/2014/798285).

Only two trials have looked at multidisciplinary rehabilitation for MS-related fatigue, Dr. de Groot said. Two studies that looked at multidisciplinary strategies that pulled in a variety of disciplines to help develop tailored fatigue management strategies saw no between-group effect when the multidisciplinary intervention was compared with nurse-provided information or with non–fatigue-related rehabilitation.

In an effort to determine whether MS-related fatigue is truly refractory to treatment, Dr. de Groot said that he and his colleagues decided to take “three steps back” to look at the individual interventions that make up a multidisciplinary approach to tackling fatigue. “So, we looked at exercise therapy, energy conservation management, and cognitive-behavioral therapy,” beginning with a literature review, he said.

Members of his research group found that effect sizes ranged from small to moderate for the three approaches, but there were methodologic problems with many of the studies; in the case of cognitive-behavioral therapy (CBT), the effect size waned over time, Dr. de Groot said. A newer randomized, controlled trial showed a relatively robust effect size of 0.52 for Internet-delivered CBT, which may provide a promising and practical approach (J Neurol Neurosurg Psychiatry. 2018 Sep;89[9]:970-6. doi: 10.1136/jnnp-2017-317463).

Looking at fatigue and societal participation, Dr. de Groot and his colleagues examined what effect aerobic training, energy conservation management, and CBT had on the two outcome measures. The three interventions were studied in three stand-alone trials, he said.

Patients were assessed at baseline, and at 8, 16, 26, and 52 weeks. The assessments were performed by a blinded researcher and were the same across trials: For fatigue, researchers used the Checklist Individual Strength–fatigue (CIS20R-fatigue), and for societal participation, they administered the Impact on Participation and Autonomy (IPA).

Each trial included 90 patients, randomized 1:1 to receive high- or low-intensity treatment. Patients had to have MS with no exacerbations within the prior 6 months and an Expanded Disability Status Scale score of 6 or less. However, the included patients had severe fatigue, with a CIS20R-fatigue subscore of 35 or higher, and the fatigue could not be attributable to such secondary causes as infection, depression, or thyroid or sleep problems. Finally, patients could not have been treated for fatigue in the 3 months prior to enrollment.

Those in the high-intensity treatment group received 12 sessions focused on the particular intervention over 4 months, provided by an expert therapist. Each type of intervention had a treatment protocol that was followed over the 4 months. Patients receiving low-intensity treatment saw an MS-specialized nurse three times over 4 months.

The aerobic training intervention had patients performing high-intensity exercise on a cycle ergometer for 30 minutes, three times weekly for 16 weeks. In addition to the 12 supervised sessions, patients also completed 36 home-based sessions. The level of intensity for each patient was personalized based on their baseline cardiopulmonary exercise test, Dr. de Groot said.

At the end of 1 year, patients in the high-intensity group and those in the low-intensity group reported virtually the same fatigue scores. Though there was an initial drop in fatigue for those in the high-intensity group, compared with baseline and with the low-intensity participants, values on the CIS20R never dropped below 35, the “severe fatigue” cutoff.

And, Dr. de Groot said, there was no effect on societal participation or in other fatigue scores. In sum, the effect size was barely significant at –0.54 (95% CI, –1.00 to –0.06), with a number needed to treat of 9.

Adherence to attempting the workouts was fairly good for participants in the high-intensity group; 74% completed the sessions, with 71% doing so at the prescribed workload. The median rate of perceived exertion on a 1-20 scale was 14.

However, the thrice-weekly exercise bouts didn’t improve aerobic fitness parameters: Neither V0₂peak, V0₂peak adjusted for body mass, nor anaerobic threshold changed for those in the high-intensity group. Peak power did increase by 11.7 watts (P = .048).

Energy conservation education, whether delivered in high- or low-intensity format, had almost no effect on fatigue scores, with a number needed to treat of 158 – a figure that is “neither significant nor clinically meaningful,” Dr. de Groot said. Other fatigue scores and societal participation levels also went unchanged.

However, CBT delivered in a series of 10 modules to address various beliefs and coping mechanisms about MS, fatigue, pain, and activity regulation did have a positive effect on fatigue. Here, the effect size was –0.79 (95% CI, –1.26 to –0.32). The number needed to treat was 3, and CIS20R values did dip below the “severe fatigue” threshold during treatment. A similar effect, Dr. de Groot said, was seen for other fatigue and quality of life measures, though societal participation scores didn’t change. No significant improvement was seen for the low-intensity CBT group.

“Severe MS-related fatigue can be reduced effectively with CBT in the short term. More research is needed on how to maintain this effect in the long term,” Dr. de Groot said. Still, “it’s currently the best treatment option,” he said.

The fact that patients reverted to their preintervention fatigue levels regardless of the intervention shows that effective treatment for MS-related fatigue should probably be ongoing, viewed more as a process than an occurrence, Dr. de Groot said.

To that end, Dr. de Groot and his colleagues are conducting a randomized, controlled trial that includes 166 MS patients with fatigue. The study has two arms: The first is a noninferiority trial comparing face-to-face CBT with e-learning delivery of the content, and the second looks at the efficacy of ongoing booster sessions after initial CBT.

An online database of randomized, controlled trials of rehabilitation for MS patients can be found at www.appeco.net.

The study was funded by Fonds NutsOhra, a private Dutch foundation. Dr. de Groot reported no relevant conflicts of interest.

[email protected]

SOURCE: de Groot V. Mult Scler. 2018;24(S2):83, Abstract 225.

BERLIN – In addition to the pain, motor and sensory impairments, and cognitive dysfunction that can stalk multiple sclerosis (MS) patients, for many, there’s also the challenge of an invisible, tough-to-quantify entity: fatigue.

©RusN/Thinkstock.com

“Approximately 80% of patients suffer from fatigue, so it’s an immense problem in MS. There’s no real clear relationship with disease severity,” Vincent de Groot, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “Despite what a lot of people think, there’s no clear or strong relationship between fatigue and the amount of physical activity people undertake daily,” he noted.

“Patients all know what we are talking about when we ask about fatigue,” but there are a variety of definitions of fatigue used in research, a fact that has limited progress in the field, said Dr. de Groot.

Primary fatigue is related to the pathophysiology of MS itself, while secondary fatigue can result from MS symptoms, such as poor sleep from spasms. Secondary fatigue can also be a side effect of MS medications; baclofen, used for spasticity, is a good example, said Dr. de Groot. “We must not underestimate how many problems these drugs can give people.”

What’s the mechanism by which MS causes primary fatigue? “The simple answer is that we do not know,” said Dr. de Groot, a physiatrist and researcher at Vrije University, Amsterdam.

Though immune-mediated fatigue had been proposed as a factor for patients with MS, Dr. de Groot said that his own lab’s work has not found any connection between fatigue levels and any immune-related biomarkers. “So I don’t think the immune hypothesis has a lot of evidence.”

Similarly, though there might be mechanistic reasons to suspect the hypothalamic-pituitary-adrenal (HPA) axis as a culprit for MS fatigue, no consistent association has been found between any markers for HPA axis disruption and fatigue ratings, Dr. de Groot said.

Newer theories center on MS-related disruptions in brain connectivity, with imaging studies now able to detect some of these disruptions in functional connectivity that correlate with fatigue. “Right now, I think this is the hypothesis to bet money on,” Dr. de Groot said.

Many factors come into play, including environmental and psychological factors, he said.

“What can we do to treat MS-related fatigue?” Though several drugs have been used, “if you carefully look at the systematic reviews, the evidence is very, very disappointing,” Dr. de Groot said. For both amantadine and modafinil, “there is no evidence that these drugs are effective,” he said, citing a systematic review and meta-analysis that found a pooled effect size of 0.07 (95% confidence interval, –0.22 to 0.37) for medications (Mult Scler Int. 2014 May; doi: 10.1155/2014/798285).

Only two trials have looked at multidisciplinary rehabilitation for MS-related fatigue, Dr. de Groot said. Two studies that looked at multidisciplinary strategies that pulled in a variety of disciplines to help develop tailored fatigue management strategies saw no between-group effect when the multidisciplinary intervention was compared with nurse-provided information or with non–fatigue-related rehabilitation.

In an effort to determine whether MS-related fatigue is truly refractory to treatment, Dr. de Groot said that he and his colleagues decided to take “three steps back” to look at the individual interventions that make up a multidisciplinary approach to tackling fatigue. “So, we looked at exercise therapy, energy conservation management, and cognitive-behavioral therapy,” beginning with a literature review, he said.

Members of his research group found that effect sizes ranged from small to moderate for the three approaches, but there were methodologic problems with many of the studies; in the case of cognitive-behavioral therapy (CBT), the effect size waned over time, Dr. de Groot said. A newer randomized, controlled trial showed a relatively robust effect size of 0.52 for Internet-delivered CBT, which may provide a promising and practical approach (J Neurol Neurosurg Psychiatry. 2018 Sep;89[9]:970-6. doi: 10.1136/jnnp-2017-317463).

Looking at fatigue and societal participation, Dr. de Groot and his colleagues examined what effect aerobic training, energy conservation management, and CBT had on the two outcome measures. The three interventions were studied in three stand-alone trials, he said.

Patients were assessed at baseline, and at 8, 16, 26, and 52 weeks. The assessments were performed by a blinded researcher and were the same across trials: For fatigue, researchers used the Checklist Individual Strength–fatigue (CIS20R-fatigue), and for societal participation, they administered the Impact on Participation and Autonomy (IPA).

Each trial included 90 patients, randomized 1:1 to receive high- or low-intensity treatment. Patients had to have MS with no exacerbations within the prior 6 months and an Expanded Disability Status Scale score of 6 or less. However, the included patients had severe fatigue, with a CIS20R-fatigue subscore of 35 or higher, and the fatigue could not be attributable to such secondary causes as infection, depression, or thyroid or sleep problems. Finally, patients could not have been treated for fatigue in the 3 months prior to enrollment.

Those in the high-intensity treatment group received 12 sessions focused on the particular intervention over 4 months, provided by an expert therapist. Each type of intervention had a treatment protocol that was followed over the 4 months. Patients receiving low-intensity treatment saw an MS-specialized nurse three times over 4 months.

The aerobic training intervention had patients performing high-intensity exercise on a cycle ergometer for 30 minutes, three times weekly for 16 weeks. In addition to the 12 supervised sessions, patients also completed 36 home-based sessions. The level of intensity for each patient was personalized based on their baseline cardiopulmonary exercise test, Dr. de Groot said.

At the end of 1 year, patients in the high-intensity group and those in the low-intensity group reported virtually the same fatigue scores. Though there was an initial drop in fatigue for those in the high-intensity group, compared with baseline and with the low-intensity participants, values on the CIS20R never dropped below 35, the “severe fatigue” cutoff.

And, Dr. de Groot said, there was no effect on societal participation or in other fatigue scores. In sum, the effect size was barely significant at –0.54 (95% CI, –1.00 to –0.06), with a number needed to treat of 9.

Adherence to attempting the workouts was fairly good for participants in the high-intensity group; 74% completed the sessions, with 71% doing so at the prescribed workload. The median rate of perceived exertion on a 1-20 scale was 14.

However, the thrice-weekly exercise bouts didn’t improve aerobic fitness parameters: Neither V0₂peak, V0₂peak adjusted for body mass, nor anaerobic threshold changed for those in the high-intensity group. Peak power did increase by 11.7 watts (P = .048).

Energy conservation education, whether delivered in high- or low-intensity format, had almost no effect on fatigue scores, with a number needed to treat of 158 – a figure that is “neither significant nor clinically meaningful,” Dr. de Groot said. Other fatigue scores and societal participation levels also went unchanged.

However, CBT delivered in a series of 10 modules to address various beliefs and coping mechanisms about MS, fatigue, pain, and activity regulation did have a positive effect on fatigue. Here, the effect size was –0.79 (95% CI, –1.26 to –0.32). The number needed to treat was 3, and CIS20R values did dip below the “severe fatigue” threshold during treatment. A similar effect, Dr. de Groot said, was seen for other fatigue and quality of life measures, though societal participation scores didn’t change. No significant improvement was seen for the low-intensity CBT group.

“Severe MS-related fatigue can be reduced effectively with CBT in the short term. More research is needed on how to maintain this effect in the long term,” Dr. de Groot said. Still, “it’s currently the best treatment option,” he said.

The fact that patients reverted to their preintervention fatigue levels regardless of the intervention shows that effective treatment for MS-related fatigue should probably be ongoing, viewed more as a process than an occurrence, Dr. de Groot said.

To that end, Dr. de Groot and his colleagues are conducting a randomized, controlled trial that includes 166 MS patients with fatigue. The study has two arms: The first is a noninferiority trial comparing face-to-face CBT with e-learning delivery of the content, and the second looks at the efficacy of ongoing booster sessions after initial CBT.

An online database of randomized, controlled trials of rehabilitation for MS patients can be found at www.appeco.net.

The study was funded by Fonds NutsOhra, a private Dutch foundation. Dr. de Groot reported no relevant conflicts of interest.

[email protected]

SOURCE: de Groot V. Mult Scler. 2018;24(S2):83, Abstract 225.

BERLIN – In addition to the pain, motor and sensory impairments, and cognitive dysfunction that can stalk multiple sclerosis (MS) patients, for many, there’s also the challenge of an invisible, tough-to-quantify entity: fatigue.

©RusN/Thinkstock.com

“Approximately 80% of patients suffer from fatigue, so it’s an immense problem in MS. There’s no real clear relationship with disease severity,” Vincent de Groot, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “Despite what a lot of people think, there’s no clear or strong relationship between fatigue and the amount of physical activity people undertake daily,” he noted.

“Patients all know what we are talking about when we ask about fatigue,” but there are a variety of definitions of fatigue used in research, a fact that has limited progress in the field, said Dr. de Groot.

Primary fatigue is related to the pathophysiology of MS itself, while secondary fatigue can result from MS symptoms, such as poor sleep from spasms. Secondary fatigue can also be a side effect of MS medications; baclofen, used for spasticity, is a good example, said Dr. de Groot. “We must not underestimate how many problems these drugs can give people.”

What’s the mechanism by which MS causes primary fatigue? “The simple answer is that we do not know,” said Dr. de Groot, a physiatrist and researcher at Vrije University, Amsterdam.

Though immune-mediated fatigue had been proposed as a factor for patients with MS, Dr. de Groot said that his own lab’s work has not found any connection between fatigue levels and any immune-related biomarkers. “So I don’t think the immune hypothesis has a lot of evidence.”

Similarly, though there might be mechanistic reasons to suspect the hypothalamic-pituitary-adrenal (HPA) axis as a culprit for MS fatigue, no consistent association has been found between any markers for HPA axis disruption and fatigue ratings, Dr. de Groot said.

Newer theories center on MS-related disruptions in brain connectivity, with imaging studies now able to detect some of these disruptions in functional connectivity that correlate with fatigue. “Right now, I think this is the hypothesis to bet money on,” Dr. de Groot said.

Many factors come into play, including environmental and psychological factors, he said.

“What can we do to treat MS-related fatigue?” Though several drugs have been used, “if you carefully look at the systematic reviews, the evidence is very, very disappointing,” Dr. de Groot said. For both amantadine and modafinil, “there is no evidence that these drugs are effective,” he said, citing a systematic review and meta-analysis that found a pooled effect size of 0.07 (95% confidence interval, –0.22 to 0.37) for medications (Mult Scler Int. 2014 May; doi: 10.1155/2014/798285).

Only two trials have looked at multidisciplinary rehabilitation for MS-related fatigue, Dr. de Groot said. Two studies that looked at multidisciplinary strategies that pulled in a variety of disciplines to help develop tailored fatigue management strategies saw no between-group effect when the multidisciplinary intervention was compared with nurse-provided information or with non–fatigue-related rehabilitation.

In an effort to determine whether MS-related fatigue is truly refractory to treatment, Dr. de Groot said that he and his colleagues decided to take “three steps back” to look at the individual interventions that make up a multidisciplinary approach to tackling fatigue. “So, we looked at exercise therapy, energy conservation management, and cognitive-behavioral therapy,” beginning with a literature review, he said.

Members of his research group found that effect sizes ranged from small to moderate for the three approaches, but there were methodologic problems with many of the studies; in the case of cognitive-behavioral therapy (CBT), the effect size waned over time, Dr. de Groot said. A newer randomized, controlled trial showed a relatively robust effect size of 0.52 for Internet-delivered CBT, which may provide a promising and practical approach (J Neurol Neurosurg Psychiatry. 2018 Sep;89[9]:970-6. doi: 10.1136/jnnp-2017-317463).

Looking at fatigue and societal participation, Dr. de Groot and his colleagues examined what effect aerobic training, energy conservation management, and CBT had on the two outcome measures. The three interventions were studied in three stand-alone trials, he said.

Patients were assessed at baseline, and at 8, 16, 26, and 52 weeks. The assessments were performed by a blinded researcher and were the same across trials: For fatigue, researchers used the Checklist Individual Strength–fatigue (CIS20R-fatigue), and for societal participation, they administered the Impact on Participation and Autonomy (IPA).

Each trial included 90 patients, randomized 1:1 to receive high- or low-intensity treatment. Patients had to have MS with no exacerbations within the prior 6 months and an Expanded Disability Status Scale score of 6 or less. However, the included patients had severe fatigue, with a CIS20R-fatigue subscore of 35 or higher, and the fatigue could not be attributable to such secondary causes as infection, depression, or thyroid or sleep problems. Finally, patients could not have been treated for fatigue in the 3 months prior to enrollment.

Those in the high-intensity treatment group received 12 sessions focused on the particular intervention over 4 months, provided by an expert therapist. Each type of intervention had a treatment protocol that was followed over the 4 months. Patients receiving low-intensity treatment saw an MS-specialized nurse three times over 4 months.

The aerobic training intervention had patients performing high-intensity exercise on a cycle ergometer for 30 minutes, three times weekly for 16 weeks. In addition to the 12 supervised sessions, patients also completed 36 home-based sessions. The level of intensity for each patient was personalized based on their baseline cardiopulmonary exercise test, Dr. de Groot said.

At the end of 1 year, patients in the high-intensity group and those in the low-intensity group reported virtually the same fatigue scores. Though there was an initial drop in fatigue for those in the high-intensity group, compared with baseline and with the low-intensity participants, values on the CIS20R never dropped below 35, the “severe fatigue” cutoff.

And, Dr. de Groot said, there was no effect on societal participation or in other fatigue scores. In sum, the effect size was barely significant at –0.54 (95% CI, –1.00 to –0.06), with a number needed to treat of 9.

Adherence to attempting the workouts was fairly good for participants in the high-intensity group; 74% completed the sessions, with 71% doing so at the prescribed workload. The median rate of perceived exertion on a 1-20 scale was 14.

However, the thrice-weekly exercise bouts didn’t improve aerobic fitness parameters: Neither V0₂peak, V0₂peak adjusted for body mass, nor anaerobic threshold changed for those in the high-intensity group. Peak power did increase by 11.7 watts (P = .048).

Energy conservation education, whether delivered in high- or low-intensity format, had almost no effect on fatigue scores, with a number needed to treat of 158 – a figure that is “neither significant nor clinically meaningful,” Dr. de Groot said. Other fatigue scores and societal participation levels also went unchanged.

However, CBT delivered in a series of 10 modules to address various beliefs and coping mechanisms about MS, fatigue, pain, and activity regulation did have a positive effect on fatigue. Here, the effect size was –0.79 (95% CI, –1.26 to –0.32). The number needed to treat was 3, and CIS20R values did dip below the “severe fatigue” threshold during treatment. A similar effect, Dr. de Groot said, was seen for other fatigue and quality of life measures, though societal participation scores didn’t change. No significant improvement was seen for the low-intensity CBT group.

“Severe MS-related fatigue can be reduced effectively with CBT in the short term. More research is needed on how to maintain this effect in the long term,” Dr. de Groot said. Still, “it’s currently the best treatment option,” he said.

The fact that patients reverted to their preintervention fatigue levels regardless of the intervention shows that effective treatment for MS-related fatigue should probably be ongoing, viewed more as a process than an occurrence, Dr. de Groot said.

To that end, Dr. de Groot and his colleagues are conducting a randomized, controlled trial that includes 166 MS patients with fatigue. The study has two arms: The first is a noninferiority trial comparing face-to-face CBT with e-learning delivery of the content, and the second looks at the efficacy of ongoing booster sessions after initial CBT.

An online database of randomized, controlled trials of rehabilitation for MS patients can be found at www.appeco.net.

The study was funded by Fonds NutsOhra, a private Dutch foundation. Dr. de Groot reported no relevant conflicts of interest.

[email protected]

SOURCE: de Groot V. Mult Scler. 2018;24(S2):83, Abstract 225.

BERLIN – The presence of infratentorial and deep white matter lesions early in the course of relapse-onset multiple sclerosis was associated with high levels of disability 30 years later in a study looking at MRI predictors.

Sara Freeman/MDedge News

Univariate predictors of an Expanded Disability Status Scale (EDSS) score of more than 3.5, which is indicative of impaired mobility after 30 years, were the presence of an IT lesion at baseline, with an odds ratio (OR) of 12.4 (95% confidence interval [CI], 3.35-3.46; P less than .001), the presence of a deep white matter (DWM) lesion 1 year after presenting with clinically-isolated syndrome (CIS; OR = 10.65; 95% CI, 2.84-38.84; P less than .001), and the presence of an infratentorial (IT) lesion 1 year post CIS presentation (OR = 11.1; 95% CI, 3.31-37.22; P less than .001). At 5 years after a CIS presentation, the EDSS score, EDSS score change, and a DWM lesion score of more than 5 were indicative of worse disability after 30 years.

There was no significant association with age of onset, gender, CIS type, baseline EDSS, or disease duration, study investigator Karen Chung, MBBS, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“As we know, approximately 85% of people with MS initially present with a clinically isolated syndrome,” said Dr. Chung, a clinical research associate at the Queen Square Multiple Sclerosis Centre in the UCL Institute of Neurology in London. She added that the long-term prognosis after CIS is very variable, with some patients developing little detectable disability over time, while others may experience considerable decline.

There have been few studies examining whether there are any MRI parameters that might help predict patients’ long-term outcomes, so the aim of the study Dr. Chung presented was to see if there were any MRI parameters that might be predictive of clinical outcome 30 years after the onset of CIS.

Dr. Chung and her coauthors examined data on 120 of 132 individuals from the First London CIS Cohort who were prospectively recruited between 1984 and 1987 and had known outcomes. They looked at prospectively gathered MRI data and EDSS data at baseline, 5, 10, 14, 20, and 30 years. MRI data were obtained for 1 year after the CIS event, and data on the lowest EDSS score after the CIS event were retrospectively determined from patient notes or recall. The cohort was predominantly female (61%), with a mean of 31.5 years at CIS onset. Around half (52%) presented with optic neuritis, 27% with a spinal cord syndrome, and 20% with a brainstem syndrome. The high percentage of patients presenting with optic neuritis may be due to the fact that one of the recruiting centers was a specialist eye hospital, Dr. Chung noted later during discussion.

The 2010 McDonald Criteria were used to determine whether patients had CIS, relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or death related to MS.

“We looked at all the MRIs available to us and quantified the T2 lesion count for whole brain as well as by location,” Dr. Chung explained. The locations considered were juxtacortical, periventricular, infratentorial, and deep white matter.

“I think it is important to remind ourselves that we have come a long way with MRI technology in the 30 years timespan,” she added, noting that there was “clearly a difference in the quality.”

Clinical outcomes at 30 years were as follows: 80 patients (67%) developed MS, of whom 35 (44%) had RRMS, 26 (33%) had SPMS, 15 (20%) had died as a result of MS, and 3 (4%) had died for unknown or unrelated causes. Of the 40 patients (33%) who remained with CIS, 10 (25%) died without developing MS.

“This is a largely untreated cohort where, within the 80 people with MS, 11 (14%) were treated with a DMT [disease-modifying treatment] at some point,” Dr. Chung reported. All DMTs used were first-line injectable agents, she observed.

EDSS scores could be obtained for 107 patients. At 30 years, people with low EDSS scores were those who remained with CIS or RRMS, and as EDSS scores increased, the severity of MS increased.

“Overall, T2 lesions were better predictors of 30-year outcome than EDSS,” Dr. Chung said. For combinations of predictors, patients who had at least one IT and one DWM lesion within 1 year of a CIS had a higher probability (94%) of having an EDSS score of more than 3.5 at 30 years than when compared with those with neither lesion (13%) and those with one DWM but no IT lesions (49%).

Looking at the best independent predictors up to 5 years, the predicted probability of an EDSS score of more than 3.5 if there were no IT lesions and fewer than five DWM lesions was 18%. But if there were no IT but more than 5 DWM lesions, the probability of disability at 30 years rose to 52%. The probabilities rose even higher to 63% if there was one or more IT and five or less DWM lesions and 90% if there was one or more IT and more than five DWM lesions.

“In this cohort, the presence of early infratentorial and deep white matter lesions following a CIS are associated with higher level of disability 30 years later,” Dr. Chung concluded. “Early predictive models can add information to risk-benefit stratification.”

During discussion, one delegate expressed concerns that these data were “not generalizable to the current situation.” This was a cohort of patients that largely wasn’t treated or if they were, treatment was delayed by more than 10 years. These data were interesting “from a historical perspective,” he argued, “but I don’t understand, how in the absence of contemporary therapies this is applicable in a way that will allow us to use this information to make prognoses for the future.”

Dr. Chung agreed, noting that this was more of a natural history study. “However, I think it is applicable in clinical practice in my opinion.

“When you have a patient presenting with a CIS, at the time of diagnosis, especially now when we can diagnose patients earlier with the new 2017 criteria, it will be helpful for the patient and ourselves to apply some of the information I presented to help perhaps in aiding decisions regarding treatment.”

The study was funded by a grant from the MS Society of Great Britain. Dr. Chung disclosed receiving honoraria from Teva, Biogen, and Roche.

SOURCE: Chung K et al. Mult Scler. 2018;24(S2):58-59, Abstract 157.

BERLIN – The presence of infratentorial and deep white matter lesions early in the course of relapse-onset multiple sclerosis was associated with high levels of disability 30 years later in a study looking at MRI predictors.

Sara Freeman/MDedge News

Univariate predictors of an Expanded Disability Status Scale (EDSS) score of more than 3.5, which is indicative of impaired mobility after 30 years, were the presence of an IT lesion at baseline, with an odds ratio (OR) of 12.4 (95% confidence interval [CI], 3.35-3.46; P less than .001), the presence of a deep white matter (DWM) lesion 1 year after presenting with clinically-isolated syndrome (CIS; OR = 10.65; 95% CI, 2.84-38.84; P less than .001), and the presence of an infratentorial (IT) lesion 1 year post CIS presentation (OR = 11.1; 95% CI, 3.31-37.22; P less than .001). At 5 years after a CIS presentation, the EDSS score, EDSS score change, and a DWM lesion score of more than 5 were indicative of worse disability after 30 years.

There was no significant association with age of onset, gender, CIS type, baseline EDSS, or disease duration, study investigator Karen Chung, MBBS, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“As we know, approximately 85% of people with MS initially present with a clinically isolated syndrome,” said Dr. Chung, a clinical research associate at the Queen Square Multiple Sclerosis Centre in the UCL Institute of Neurology in London. She added that the long-term prognosis after CIS is very variable, with some patients developing little detectable disability over time, while others may experience considerable decline.

There have been few studies examining whether there are any MRI parameters that might help predict patients’ long-term outcomes, so the aim of the study Dr. Chung presented was to see if there were any MRI parameters that might be predictive of clinical outcome 30 years after the onset of CIS.

Dr. Chung and her coauthors examined data on 120 of 132 individuals from the First London CIS Cohort who were prospectively recruited between 1984 and 1987 and had known outcomes. They looked at prospectively gathered MRI data and EDSS data at baseline, 5, 10, 14, 20, and 30 years. MRI data were obtained for 1 year after the CIS event, and data on the lowest EDSS score after the CIS event were retrospectively determined from patient notes or recall. The cohort was predominantly female (61%), with a mean of 31.5 years at CIS onset. Around half (52%) presented with optic neuritis, 27% with a spinal cord syndrome, and 20% with a brainstem syndrome. The high percentage of patients presenting with optic neuritis may be due to the fact that one of the recruiting centers was a specialist eye hospital, Dr. Chung noted later during discussion.

The 2010 McDonald Criteria were used to determine whether patients had CIS, relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or death related to MS.

“We looked at all the MRIs available to us and quantified the T2 lesion count for whole brain as well as by location,” Dr. Chung explained. The locations considered were juxtacortical, periventricular, infratentorial, and deep white matter.

“I think it is important to remind ourselves that we have come a long way with MRI technology in the 30 years timespan,” she added, noting that there was “clearly a difference in the quality.”

Clinical outcomes at 30 years were as follows: 80 patients (67%) developed MS, of whom 35 (44%) had RRMS, 26 (33%) had SPMS, 15 (20%) had died as a result of MS, and 3 (4%) had died for unknown or unrelated causes. Of the 40 patients (33%) who remained with CIS, 10 (25%) died without developing MS.

“This is a largely untreated cohort where, within the 80 people with MS, 11 (14%) were treated with a DMT [disease-modifying treatment] at some point,” Dr. Chung reported. All DMTs used were first-line injectable agents, she observed.

EDSS scores could be obtained for 107 patients. At 30 years, people with low EDSS scores were those who remained with CIS or RRMS, and as EDSS scores increased, the severity of MS increased.

“Overall, T2 lesions were better predictors of 30-year outcome than EDSS,” Dr. Chung said. For combinations of predictors, patients who had at least one IT and one DWM lesion within 1 year of a CIS had a higher probability (94%) of having an EDSS score of more than 3.5 at 30 years than when compared with those with neither lesion (13%) and those with one DWM but no IT lesions (49%).

Looking at the best independent predictors up to 5 years, the predicted probability of an EDSS score of more than 3.5 if there were no IT lesions and fewer than five DWM lesions was 18%. But if there were no IT but more than 5 DWM lesions, the probability of disability at 30 years rose to 52%. The probabilities rose even higher to 63% if there was one or more IT and five or less DWM lesions and 90% if there was one or more IT and more than five DWM lesions.

“In this cohort, the presence of early infratentorial and deep white matter lesions following a CIS are associated with higher level of disability 30 years later,” Dr. Chung concluded. “Early predictive models can add information to risk-benefit stratification.”

During discussion, one delegate expressed concerns that these data were “not generalizable to the current situation.” This was a cohort of patients that largely wasn’t treated or if they were, treatment was delayed by more than 10 years. These data were interesting “from a historical perspective,” he argued, “but I don’t understand, how in the absence of contemporary therapies this is applicable in a way that will allow us to use this information to make prognoses for the future.”

Dr. Chung agreed, noting that this was more of a natural history study. “However, I think it is applicable in clinical practice in my opinion.

“When you have a patient presenting with a CIS, at the time of diagnosis, especially now when we can diagnose patients earlier with the new 2017 criteria, it will be helpful for the patient and ourselves to apply some of the information I presented to help perhaps in aiding decisions regarding treatment.”

The study was funded by a grant from the MS Society of Great Britain. Dr. Chung disclosed receiving honoraria from Teva, Biogen, and Roche.

SOURCE: Chung K et al. Mult Scler. 2018;24(S2):58-59, Abstract 157.

BERLIN – The presence of infratentorial and deep white matter lesions early in the course of relapse-onset multiple sclerosis was associated with high levels of disability 30 years later in a study looking at MRI predictors.

Sara Freeman/MDedge News

Univariate predictors of an Expanded Disability Status Scale (EDSS) score of more than 3.5, which is indicative of impaired mobility after 30 years, were the presence of an IT lesion at baseline, with an odds ratio (OR) of 12.4 (95% confidence interval [CI], 3.35-3.46; P less than .001), the presence of a deep white matter (DWM) lesion 1 year after presenting with clinically-isolated syndrome (CIS; OR = 10.65; 95% CI, 2.84-38.84; P less than .001), and the presence of an infratentorial (IT) lesion 1 year post CIS presentation (OR = 11.1; 95% CI, 3.31-37.22; P less than .001). At 5 years after a CIS presentation, the EDSS score, EDSS score change, and a DWM lesion score of more than 5 were indicative of worse disability after 30 years.

There was no significant association with age of onset, gender, CIS type, baseline EDSS, or disease duration, study investigator Karen Chung, MBBS, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“As we know, approximately 85% of people with MS initially present with a clinically isolated syndrome,” said Dr. Chung, a clinical research associate at the Queen Square Multiple Sclerosis Centre in the UCL Institute of Neurology in London. She added that the long-term prognosis after CIS is very variable, with some patients developing little detectable disability over time, while others may experience considerable decline.

There have been few studies examining whether there are any MRI parameters that might help predict patients’ long-term outcomes, so the aim of the study Dr. Chung presented was to see if there were any MRI parameters that might be predictive of clinical outcome 30 years after the onset of CIS.

Dr. Chung and her coauthors examined data on 120 of 132 individuals from the First London CIS Cohort who were prospectively recruited between 1984 and 1987 and had known outcomes. They looked at prospectively gathered MRI data and EDSS data at baseline, 5, 10, 14, 20, and 30 years. MRI data were obtained for 1 year after the CIS event, and data on the lowest EDSS score after the CIS event were retrospectively determined from patient notes or recall. The cohort was predominantly female (61%), with a mean of 31.5 years at CIS onset. Around half (52%) presented with optic neuritis, 27% with a spinal cord syndrome, and 20% with a brainstem syndrome. The high percentage of patients presenting with optic neuritis may be due to the fact that one of the recruiting centers was a specialist eye hospital, Dr. Chung noted later during discussion.

The 2010 McDonald Criteria were used to determine whether patients had CIS, relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or death related to MS.

“We looked at all the MRIs available to us and quantified the T2 lesion count for whole brain as well as by location,” Dr. Chung explained. The locations considered were juxtacortical, periventricular, infratentorial, and deep white matter.

“I think it is important to remind ourselves that we have come a long way with MRI technology in the 30 years timespan,” she added, noting that there was “clearly a difference in the quality.”

Clinical outcomes at 30 years were as follows: 80 patients (67%) developed MS, of whom 35 (44%) had RRMS, 26 (33%) had SPMS, 15 (20%) had died as a result of MS, and 3 (4%) had died for unknown or unrelated causes. Of the 40 patients (33%) who remained with CIS, 10 (25%) died without developing MS.

“This is a largely untreated cohort where, within the 80 people with MS, 11 (14%) were treated with a DMT [disease-modifying treatment] at some point,” Dr. Chung reported. All DMTs used were first-line injectable agents, she observed.

EDSS scores could be obtained for 107 patients. At 30 years, people with low EDSS scores were those who remained with CIS or RRMS, and as EDSS scores increased, the severity of MS increased.

“Overall, T2 lesions were better predictors of 30-year outcome than EDSS,” Dr. Chung said. For combinations of predictors, patients who had at least one IT and one DWM lesion within 1 year of a CIS had a higher probability (94%) of having an EDSS score of more than 3.5 at 30 years than when compared with those with neither lesion (13%) and those with one DWM but no IT lesions (49%).

Looking at the best independent predictors up to 5 years, the predicted probability of an EDSS score of more than 3.5 if there were no IT lesions and fewer than five DWM lesions was 18%. But if there were no IT but more than 5 DWM lesions, the probability of disability at 30 years rose to 52%. The probabilities rose even higher to 63% if there was one or more IT and five or less DWM lesions and 90% if there was one or more IT and more than five DWM lesions.

“In this cohort, the presence of early infratentorial and deep white matter lesions following a CIS are associated with higher level of disability 30 years later,” Dr. Chung concluded. “Early predictive models can add information to risk-benefit stratification.”

During discussion, one delegate expressed concerns that these data were “not generalizable to the current situation.” This was a cohort of patients that largely wasn’t treated or if they were, treatment was delayed by more than 10 years. These data were interesting “from a historical perspective,” he argued, “but I don’t understand, how in the absence of contemporary therapies this is applicable in a way that will allow us to use this information to make prognoses for the future.”

Dr. Chung agreed, noting that this was more of a natural history study. “However, I think it is applicable in clinical practice in my opinion.

“When you have a patient presenting with a CIS, at the time of diagnosis, especially now when we can diagnose patients earlier with the new 2017 criteria, it will be helpful for the patient and ourselves to apply some of the information I presented to help perhaps in aiding decisions regarding treatment.”

The study was funded by a grant from the MS Society of Great Britain. Dr. Chung disclosed receiving honoraria from Teva, Biogen, and Roche.

SOURCE: Chung K et al. Mult Scler. 2018;24(S2):58-59, Abstract 157.

The National Multiple Sclerosis (MS) Society has developed recommendations for the identification and management of cognitive impairment in MS. The recommendations, which were endorsed by the Consortium of MS Centers and the International MS Cognition Society, were published online ahead of print October 10 in Multiple Sclerosis Journal.

Cognitive change may affect between 34% and 65% of adults with MS. Decreases in information processing and memory are the most common changes, and cognitive impairment may arise before MRI abnormalities that indicate MS. These changes can affect patients’ ability to work, drive, manage money, and participate in activities.

Patients and Clinicians Need Information

Patients and caregivers should receive information about common cognitive changes in MS and how they affect everyday life, said Rosalind Kalb, PhD, Vice President of the Professional Resource Center at the National MS Society in New York, and coauthors. Patients and caregivers also should be told about the high prevalence of cognitive symptoms in MS and the need for ongoing assessments. Similarly, clinicians need information about how cognitive impairments affect medical decision-making and adherence, said the authors. Clinicians also need referral resources for cognitive assessment and treatment.

All adults and children age 8 or older diagnosed with MS should, as a minimum, undergo early baseline screening with the Symbol Digit Modalities Test (SDMT) or another validated screening tool, according to the recommendations. These patients should be reassessed with the same instrument annually or more often, as needed, to detect disease activity, assess for treatment effects or relapse recovery, monitor progression of cognitive impairment, and screen for new cognitive problems.

In addition to the SDMT, screening tools that have been validated in patients with MS include the Processing Speed Test, Computerized Speed Cognitive Test, MS Neuropsychological Screening Questionnaire, Brief International Cognitive Assessment for MS, Brief Repeatable Neuropsychological Battery, and Minimal Assessment of Cognitive Function in MS.

Interventions May Improve or Maintain Function

An adult who tests positive for cognitive impairment on initial screening should undergo a more comprehensive assessment, especially if the person has comorbidities that raise concerns or is applying for disability due to cognitive impairment. A child with an unexplained change in school performance should receive a neuropsychologic evaluation, said Dr. Kalb and colleagues.

Furthermore, adults and children should be offered remedial interventions or accommodations to improve function at home, work, or school. Appropriately trained professionals should deliver these interventions to address “objectively measured deficits in attention, processing speed, memory and learning, and performance of everyday functional tasks,” said the authors. Clinicians can consider contextualized treatment (eg, self-generated learning tasks) and noncontextualized treatment (eg, memory-retrieval practice and computer-based attention interventions) for remediation of everyday activities, according to the recommendations.

Emerging research supports the potential for exercise to benefit cognitive processing speed in patients with MS. Trials of symptomatic pharmacologic treatments for cognitive impairment related to MS have yielded inconclusive results, however. In addition, few pivotal trials of disease-modifying therapies have incorporated cognitive outcome measures.

—Erik Greb

Suggested Reading

Kalb R, Beier M, Benedict RH, et al. Recommendations for cognitive screening and management in multiple sclerosis care. Mult Scler. 2018 Oct 10 [Epub ahead of print].

The National Multiple Sclerosis (MS) Society has developed recommendations for the identification and management of cognitive impairment in MS. The recommendations, which were endorsed by the Consortium of MS Centers and the International MS Cognition Society, were published online ahead of print October 10 in Multiple Sclerosis Journal.

Cognitive change may affect between 34% and 65% of adults with MS. Decreases in information processing and memory are the most common changes, and cognitive impairment may arise before MRI abnormalities that indicate MS. These changes can affect patients’ ability to work, drive, manage money, and participate in activities.

Patients and Clinicians Need Information

Patients and caregivers should receive information about common cognitive changes in MS and how they affect everyday life, said Rosalind Kalb, PhD, Vice President of the Professional Resource Center at the National MS Society in New York, and coauthors. Patients and caregivers also should be told about the high prevalence of cognitive symptoms in MS and the need for ongoing assessments. Similarly, clinicians need information about how cognitive impairments affect medical decision-making and adherence, said the authors. Clinicians also need referral resources for cognitive assessment and treatment.

All adults and children age 8 or older diagnosed with MS should, as a minimum, undergo early baseline screening with the Symbol Digit Modalities Test (SDMT) or another validated screening tool, according to the recommendations. These patients should be reassessed with the same instrument annually or more often, as needed, to detect disease activity, assess for treatment effects or relapse recovery, monitor progression of cognitive impairment, and screen for new cognitive problems.

In addition to the SDMT, screening tools that have been validated in patients with MS include the Processing Speed Test, Computerized Speed Cognitive Test, MS Neuropsychological Screening Questionnaire, Brief International Cognitive Assessment for MS, Brief Repeatable Neuropsychological Battery, and Minimal Assessment of Cognitive Function in MS.

Interventions May Improve or Maintain Function

An adult who tests positive for cognitive impairment on initial screening should undergo a more comprehensive assessment, especially if the person has comorbidities that raise concerns or is applying for disability due to cognitive impairment. A child with an unexplained change in school performance should receive a neuropsychologic evaluation, said Dr. Kalb and colleagues.

Furthermore, adults and children should be offered remedial interventions or accommodations to improve function at home, work, or school. Appropriately trained professionals should deliver these interventions to address “objectively measured deficits in attention, processing speed, memory and learning, and performance of everyday functional tasks,” said the authors. Clinicians can consider contextualized treatment (eg, self-generated learning tasks) and noncontextualized treatment (eg, memory-retrieval practice and computer-based attention interventions) for remediation of everyday activities, according to the recommendations.

Emerging research supports the potential for exercise to benefit cognitive processing speed in patients with MS. Trials of symptomatic pharmacologic treatments for cognitive impairment related to MS have yielded inconclusive results, however. In addition, few pivotal trials of disease-modifying therapies have incorporated cognitive outcome measures.

—Erik Greb

Suggested Reading

Kalb R, Beier M, Benedict RH, et al. Recommendations for cognitive screening and management in multiple sclerosis care. Mult Scler. 2018 Oct 10 [Epub ahead of print].

The National Multiple Sclerosis (MS) Society has developed recommendations for the identification and management of cognitive impairment in MS. The recommendations, which were endorsed by the Consortium of MS Centers and the International MS Cognition Society, were published online ahead of print October 10 in Multiple Sclerosis Journal.

Cognitive change may affect between 34% and 65% of adults with MS. Decreases in information processing and memory are the most common changes, and cognitive impairment may arise before MRI abnormalities that indicate MS. These changes can affect patients’ ability to work, drive, manage money, and participate in activities.

Patients and Clinicians Need Information

Patients and caregivers should receive information about common cognitive changes in MS and how they affect everyday life, said Rosalind Kalb, PhD, Vice President of the Professional Resource Center at the National MS Society in New York, and coauthors. Patients and caregivers also should be told about the high prevalence of cognitive symptoms in MS and the need for ongoing assessments. Similarly, clinicians need information about how cognitive impairments affect medical decision-making and adherence, said the authors. Clinicians also need referral resources for cognitive assessment and treatment.

All adults and children age 8 or older diagnosed with MS should, as a minimum, undergo early baseline screening with the Symbol Digit Modalities Test (SDMT) or another validated screening tool, according to the recommendations. These patients should be reassessed with the same instrument annually or more often, as needed, to detect disease activity, assess for treatment effects or relapse recovery, monitor progression of cognitive impairment, and screen for new cognitive problems.

In addition to the SDMT, screening tools that have been validated in patients with MS include the Processing Speed Test, Computerized Speed Cognitive Test, MS Neuropsychological Screening Questionnaire, Brief International Cognitive Assessment for MS, Brief Repeatable Neuropsychological Battery, and Minimal Assessment of Cognitive Function in MS.

Interventions May Improve or Maintain Function

An adult who tests positive for cognitive impairment on initial screening should undergo a more comprehensive assessment, especially if the person has comorbidities that raise concerns or is applying for disability due to cognitive impairment. A child with an unexplained change in school performance should receive a neuropsychologic evaluation, said Dr. Kalb and colleagues.

Furthermore, adults and children should be offered remedial interventions or accommodations to improve function at home, work, or school. Appropriately trained professionals should deliver these interventions to address “objectively measured deficits in attention, processing speed, memory and learning, and performance of everyday functional tasks,” said the authors. Clinicians can consider contextualized treatment (eg, self-generated learning tasks) and noncontextualized treatment (eg, memory-retrieval practice and computer-based attention interventions) for remediation of everyday activities, according to the recommendations.

Emerging research supports the potential for exercise to benefit cognitive processing speed in patients with MS. Trials of symptomatic pharmacologic treatments for cognitive impairment related to MS have yielded inconclusive results, however. In addition, few pivotal trials of disease-modifying therapies have incorporated cognitive outcome measures.

—Erik Greb

Suggested Reading

Kalb R, Beier M, Benedict RH, et al. Recommendations for cognitive screening and management in multiple sclerosis care. Mult Scler. 2018 Oct 10 [Epub ahead of print].

BERLIN – At least one-third of patients being treated with fingolimod (Gilenya) for multiple sclerosis (MS) will relapse after stopping the drug, according to data from two “real-world” studies reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis, one of which was undertaken in pregnant women.

Sara Freeman/MDedge News

In a retrospective analysis of 110 MS patients who discontinued fingolimod from a 433-patient cohort, around 35% experienced a recurrence of disease activity after fingolimod withdrawal. Study investigator Nuria Cerda, MD, of the Neurologic Clinic and Polyclinic at University Hospital Basel (Switzerland), reported that risk factors for increased disease activity were younger rather than older age at MS diagnosis (P = .01) and at discontinuation (P less than .0001), having had a shorter rather than longer disease duration (P = .01), and evidence of MRI-confirmed disease activity occurring while on treatment with fingolimod (P = .02).

“We aimed to describe the frequency of recurrence of disease activity after fingolimod discontinuation in a real-world cohort of MS patients,” Dr. Cerda said. She noted that there were conflicting data on reappearing disease activity after stopping the drug. Case reports and observational data suggest a frequency of 10%-53%, but post hoc analyses of phase 3 trials with fingolimod have not found any higher risk for recurrence versus placebo.

The study also compared “demographic and clinical characteristics in patients with and without recurrence of disease activity, in order to identify possible risk factors for reactivation of the disease.”

The patients included in the study had been treated with fingolimod for a median of 24 months (interquartile range, 10-43 months) and experienced 118 discontinuation events between them. The majority (n = 81) had relapsing-remitting MS, and the remainder (n = 19) were in transition from RRMS to secondary progressive MS.

The mean age at discontinuation was 40 years and, while 60% of patients switched to another disease-modifying therapy (DMT), 40% did not receive further DMT. The reasons for discontinuation were classified as being from disease activity in 44%, side effects in 21%, pregnancy or childbearing preferences in 16%, noncompliance in 2%, and other reasons in 17%.

Recurrence of disease activity was defined as clinical symptoms, gadolinium-enhancing (Gd+) lesions on MRI, or both, within 6 months of stopping fingolimod. This was seen in 38 patients with 41 events, giving a rate of recurrence of 35%. Of these: “almost 60% had clinical and MRI activity, almost 30% had clinical activity only without Gd+ lesions on MRI, and 12% had MRI activity only without ever having a relapse,” Dr. Cerda said. In those who relapsed, the recurrence took a median 8 weeks to happen after fingolimod discontinuation.

A further definition of severe recurrence of disease activity also was used, defined as either a worsening in the Expanded Disability Status Scale (EDSS) score of more than 2 points (signifying a severe relapse) with or without pronounced MRI activity with at least five cerebral Gd+ lesions within 6 months of fingolimod withdrawal. Thirteen severe events were seen in 11 patients, giving a frequency of approximately 11%. Dr. Cerda reported that patients with severe recurrence were significantly younger at MS diagnosis than were those who did not experience recurrence (P = .003). A trend toward a higher annualized relapse rate (ARR) was seen in patients with severely active versus inactive disease (0.84 vs. 0.54), but this was not statistically significant. In addition, “confirmed disability worsening of 1 EDSS point or more was observed in about 3%.”

Relapse rates coming off fingolimod before or during pregnancy

In another study, which used German registry data on 129 pregnancies that occurred around or after the time of fingolimod withdrawal, up to 56% of women who stopped fingolimod before pregnancy experienced a relapse during pregnancy versus 29% of those who stopped fingolimod upon a positive pregnancy test.

Sara Freeman/MDedge News

In a comparison of women who stopped fingolimod 1 year to 61 days before their last menstrual period against those who stopped less than 60 days prior to or after their last menstrual period, relapse rates were higher during the first (25.8% for early withdrawal vs. 12.5% with late withdrawal) and second trimesters (32.3% vs. 11.5%) than in the third (9.7% vs. 10.4%), Spalmai Hemat, MD, of the department of neurology at St. Josef Hospital, Ruhr University of Bochum (Germany) reported at the congress.

Relapse rates at 6 months postpartum proved to be similar at 36.7% for women who stopped fingolimod before their pregnancy and 38% in those who stopped later. Difference in the percentage of women experiencing disability progression during pregnancy did not prove to be statistically significant for stopping fingolimod before pregnancy (22.7%) vs. stopping later (11.1%; P = .283), while the 23.8% rate of disability progression after pregnancy among women who stopped the drug later versus 13.6% seen with stopping before was also not statistically significant (P = .31). Relapse during pregnancy was the only significant predictor for relapses postpartum.

“The large majority of women did not experience permanent disability,” Dr. Hemat said, but noted that as many as 10%-20% could experience substantial EDSS worsening (2 or more points) at 6 months postpartum.

Dr. Hemat concluded that more data were needed to see if reintroduction of fingolimod very soon after birth, such as within the first 2 weeks, could reduce the postpartum relapse risk.

Dr. Hemat and Dr. Cerda had no relevant disclosures.

SOURCES: Cerda N et al. Mult Scler. 2018;24(S2):73-4, Abstract 206; Hemat S et al. Mult Scler. 2018;24(S2):74-5, Abstract 207.

BERLIN – At least one-third of patients being treated with fingolimod (Gilenya) for multiple sclerosis (MS) will relapse after stopping the drug, according to data from two “real-world” studies reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis, one of which was undertaken in pregnant women.

Sara Freeman/MDedge News

In a retrospective analysis of 110 MS patients who discontinued fingolimod from a 433-patient cohort, around 35% experienced a recurrence of disease activity after fingolimod withdrawal. Study investigator Nuria Cerda, MD, of the Neurologic Clinic and Polyclinic at University Hospital Basel (Switzerland), reported that risk factors for increased disease activity were younger rather than older age at MS diagnosis (P = .01) and at discontinuation (P less than .0001), having had a shorter rather than longer disease duration (P = .01), and evidence of MRI-confirmed disease activity occurring while on treatment with fingolimod (P = .02).

“We aimed to describe the frequency of recurrence of disease activity after fingolimod discontinuation in a real-world cohort of MS patients,” Dr. Cerda said. She noted that there were conflicting data on reappearing disease activity after stopping the drug. Case reports and observational data suggest a frequency of 10%-53%, but post hoc analyses of phase 3 trials with fingolimod have not found any higher risk for recurrence versus placebo.

The study also compared “demographic and clinical characteristics in patients with and without recurrence of disease activity, in order to identify possible risk factors for reactivation of the disease.”

The patients included in the study had been treated with fingolimod for a median of 24 months (interquartile range, 10-43 months) and experienced 118 discontinuation events between them. The majority (n = 81) had relapsing-remitting MS, and the remainder (n = 19) were in transition from RRMS to secondary progressive MS.

The mean age at discontinuation was 40 years and, while 60% of patients switched to another disease-modifying therapy (DMT), 40% did not receive further DMT. The reasons for discontinuation were classified as being from disease activity in 44%, side effects in 21%, pregnancy or childbearing preferences in 16%, noncompliance in 2%, and other reasons in 17%.

Recurrence of disease activity was defined as clinical symptoms, gadolinium-enhancing (Gd+) lesions on MRI, or both, within 6 months of stopping fingolimod. This was seen in 38 patients with 41 events, giving a rate of recurrence of 35%. Of these: “almost 60% had clinical and MRI activity, almost 30% had clinical activity only without Gd+ lesions on MRI, and 12% had MRI activity only without ever having a relapse,” Dr. Cerda said. In those who relapsed, the recurrence took a median 8 weeks to happen after fingolimod discontinuation.

A further definition of severe recurrence of disease activity also was used, defined as either a worsening in the Expanded Disability Status Scale (EDSS) score of more than 2 points (signifying a severe relapse) with or without pronounced MRI activity with at least five cerebral Gd+ lesions within 6 months of fingolimod withdrawal. Thirteen severe events were seen in 11 patients, giving a frequency of approximately 11%. Dr. Cerda reported that patients with severe recurrence were significantly younger at MS diagnosis than were those who did not experience recurrence (P = .003). A trend toward a higher annualized relapse rate (ARR) was seen in patients with severely active versus inactive disease (0.84 vs. 0.54), but this was not statistically significant. In addition, “confirmed disability worsening of 1 EDSS point or more was observed in about 3%.”

Relapse rates coming off fingolimod before or during pregnancy

In another study, which used German registry data on 129 pregnancies that occurred around or after the time of fingolimod withdrawal, up to 56% of women who stopped fingolimod before pregnancy experienced a relapse during pregnancy versus 29% of those who stopped fingolimod upon a positive pregnancy test.

Sara Freeman/MDedge News

In a comparison of women who stopped fingolimod 1 year to 61 days before their last menstrual period against those who stopped less than 60 days prior to or after their last menstrual period, relapse rates were higher during the first (25.8% for early withdrawal vs. 12.5% with late withdrawal) and second trimesters (32.3% vs. 11.5%) than in the third (9.7% vs. 10.4%), Spalmai Hemat, MD, of the department of neurology at St. Josef Hospital, Ruhr University of Bochum (Germany) reported at the congress.

Relapse rates at 6 months postpartum proved to be similar at 36.7% for women who stopped fingolimod before their pregnancy and 38% in those who stopped later. Difference in the percentage of women experiencing disability progression during pregnancy did not prove to be statistically significant for stopping fingolimod before pregnancy (22.7%) vs. stopping later (11.1%; P = .283), while the 23.8% rate of disability progression after pregnancy among women who stopped the drug later versus 13.6% seen with stopping before was also not statistically significant (P = .31). Relapse during pregnancy was the only significant predictor for relapses postpartum.

“The large majority of women did not experience permanent disability,” Dr. Hemat said, but noted that as many as 10%-20% could experience substantial EDSS worsening (2 or more points) at 6 months postpartum.

Dr. Hemat concluded that more data were needed to see if reintroduction of fingolimod very soon after birth, such as within the first 2 weeks, could reduce the postpartum relapse risk.

Dr. Hemat and Dr. Cerda had no relevant disclosures.

SOURCES: Cerda N et al. Mult Scler. 2018;24(S2):73-4, Abstract 206; Hemat S et al. Mult Scler. 2018;24(S2):74-5, Abstract 207.

BERLIN – At least one-third of patients being treated with fingolimod (Gilenya) for multiple sclerosis (MS) will relapse after stopping the drug, according to data from two “real-world” studies reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis, one of which was undertaken in pregnant women.

Sara Freeman/MDedge News

In a retrospective analysis of 110 MS patients who discontinued fingolimod from a 433-patient cohort, around 35% experienced a recurrence of disease activity after fingolimod withdrawal. Study investigator Nuria Cerda, MD, of the Neurologic Clinic and Polyclinic at University Hospital Basel (Switzerland), reported that risk factors for increased disease activity were younger rather than older age at MS diagnosis (P = .01) and at discontinuation (P less than .0001), having had a shorter rather than longer disease duration (P = .01), and evidence of MRI-confirmed disease activity occurring while on treatment with fingolimod (P = .02).

“We aimed to describe the frequency of recurrence of disease activity after fingolimod discontinuation in a real-world cohort of MS patients,” Dr. Cerda said. She noted that there were conflicting data on reappearing disease activity after stopping the drug. Case reports and observational data suggest a frequency of 10%-53%, but post hoc analyses of phase 3 trials with fingolimod have not found any higher risk for recurrence versus placebo.

The study also compared “demographic and clinical characteristics in patients with and without recurrence of disease activity, in order to identify possible risk factors for reactivation of the disease.”

The patients included in the study had been treated with fingolimod for a median of 24 months (interquartile range, 10-43 months) and experienced 118 discontinuation events between them. The majority (n = 81) had relapsing-remitting MS, and the remainder (n = 19) were in transition from RRMS to secondary progressive MS.

The mean age at discontinuation was 40 years and, while 60% of patients switched to another disease-modifying therapy (DMT), 40% did not receive further DMT. The reasons for discontinuation were classified as being from disease activity in 44%, side effects in 21%, pregnancy or childbearing preferences in 16%, noncompliance in 2%, and other reasons in 17%.

Recurrence of disease activity was defined as clinical symptoms, gadolinium-enhancing (Gd+) lesions on MRI, or both, within 6 months of stopping fingolimod. This was seen in 38 patients with 41 events, giving a rate of recurrence of 35%. Of these: “almost 60% had clinical and MRI activity, almost 30% had clinical activity only without Gd+ lesions on MRI, and 12% had MRI activity only without ever having a relapse,” Dr. Cerda said. In those who relapsed, the recurrence took a median 8 weeks to happen after fingolimod discontinuation.

A further definition of severe recurrence of disease activity also was used, defined as either a worsening in the Expanded Disability Status Scale (EDSS) score of more than 2 points (signifying a severe relapse) with or without pronounced MRI activity with at least five cerebral Gd+ lesions within 6 months of fingolimod withdrawal. Thirteen severe events were seen in 11 patients, giving a frequency of approximately 11%. Dr. Cerda reported that patients with severe recurrence were significantly younger at MS diagnosis than were those who did not experience recurrence (P = .003). A trend toward a higher annualized relapse rate (ARR) was seen in patients with severely active versus inactive disease (0.84 vs. 0.54), but this was not statistically significant. In addition, “confirmed disability worsening of 1 EDSS point or more was observed in about 3%.”

Relapse rates coming off fingolimod before or during pregnancy

In another study, which used German registry data on 129 pregnancies that occurred around or after the time of fingolimod withdrawal, up to 56% of women who stopped fingolimod before pregnancy experienced a relapse during pregnancy versus 29% of those who stopped fingolimod upon a positive pregnancy test.

Sara Freeman/MDedge News

In a comparison of women who stopped fingolimod 1 year to 61 days before their last menstrual period against those who stopped less than 60 days prior to or after their last menstrual period, relapse rates were higher during the first (25.8% for early withdrawal vs. 12.5% with late withdrawal) and second trimesters (32.3% vs. 11.5%) than in the third (9.7% vs. 10.4%), Spalmai Hemat, MD, of the department of neurology at St. Josef Hospital, Ruhr University of Bochum (Germany) reported at the congress.

Relapse rates at 6 months postpartum proved to be similar at 36.7% for women who stopped fingolimod before their pregnancy and 38% in those who stopped later. Difference in the percentage of women experiencing disability progression during pregnancy did not prove to be statistically significant for stopping fingolimod before pregnancy (22.7%) vs. stopping later (11.1%; P = .283), while the 23.8% rate of disability progression after pregnancy among women who stopped the drug later versus 13.6% seen with stopping before was also not statistically significant (P = .31). Relapse during pregnancy was the only significant predictor for relapses postpartum.

“The large majority of women did not experience permanent disability,” Dr. Hemat said, but noted that as many as 10%-20% could experience substantial EDSS worsening (2 or more points) at 6 months postpartum.

Dr. Hemat concluded that more data were needed to see if reintroduction of fingolimod very soon after birth, such as within the first 2 weeks, could reduce the postpartum relapse risk.

Dr. Hemat and Dr. Cerda had no relevant disclosures.

SOURCES: Cerda N et al. Mult Scler. 2018;24(S2):73-4, Abstract 206; Hemat S et al. Mult Scler. 2018;24(S2):74-5, Abstract 207.

BERLIN – In children with an incident acquired demyelinating episode, the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) weighs against an eventual diagnosis of multiple sclerosis, especially if the child is younger than 11 years.

“Anti-MOG antibodies are present in about 30% of children with acquired demyelinating syndromes,” Giulia Fadda, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “About 80% experience a monophasic disease course.”

The antibodies are found in almost all children who have a relapsing non-MS demyelinating disease, said Dr. Fadda, who is a postdoctoral research fellow at the University of Pennsylvania, Philadelphia. But when the antibodies are present in children with an MS diagnosis, they identify a very specific subset with atypical clinical and imaging features.

The large prospective Canadian Pediatric Demyelinating Disease Study provided the sample for the study she presented at ECTRIMS. Children are recruited into the study soon after a first demyelinating event, and they are followed clinically, serologically, and with regular brain MRI.


The cohort in Dr. Fadda’s study comprised 275 children who were a mean of about 11 years old at symptom onset. The mean clinical follow-up was 6.7 years; the mean serologic follow-up, 4 years, and the mean imaging follow-up, 3.5 years. The study examined 1,368 serum samples and 1,459 MRI scans.

Overall, 32% of the children were positive for anti-MOG antibodies. Positivity was not associated with sex, but children with antibodies were significantly younger than those without (7 vs. 12 years). In fact, 77% of anti-MOG–positive children were younger than 11 years; just 15% of older children were positive for the antibodies.

Anti-MOG positivity was also associated with certain clinical phenotypes. Among positive children, 40% presented with optic neuritis, 37% with acute disseminated encephalomyelitis, and 14% with transverse myelitis; the rest had other phenotypes. Optic neuritis was significantly less common among antibody-negative patients (22%), as was encephalomyelitis (17%). Transverse myelitis was significantly more common (31%).

The analysis of MRI scans was stratified according to age younger than 11 years and 11 years and older. “The first thing we noticed among the younger MOG-positive children is that they had a high number of lesions, which were more commonly ill-defined, diffuse, and bilateral,” Dr. Fadda said. “Almost all the brain areas were affected, with a slight preponderance of thalamic and juxtacortical lesions. Among the MOG-negative children, lesions were more often perpendicular to the major axis of the corpus callosum.”

Among the older MOG antibody–positive children, the diffuse pattern was rarer, and the lesions were frequently cerebellar. “But by far, the features that best differentiated positivity from negativity were black holes and enhancing lesions, which we saw in a high proportion of children without the antibodies” at 73% and 49%, respectively.

Over a mean imaging follow-up period of 4 years, lesions were more likely to resolve completely in antibody-positive children than in those without antibodies (50% vs. 21%). Serologically, children who were MOG-antibody negative at baseline were likely to stay that way, with 99% remaining seronegative. Positive children, on the other hand, were significantly more likely to change serologic status, with 56% turning negative and 8% serologically fluctuating over the follow-up period; only 36% remained persistently seropositive. Persistent positive status was significantly associated with younger age (7 vs. 9 years) and an optic neuritis presentation (62% vs. 27%).

Most children (81%) who were antibody positive at baseline experienced no relapses. Among the 16 children who did experience a clinical relapse, the mean time to a second event was about 1 year. Nine of these children stayed persistently positive, while five seroconverted and two had fluctuating status.

Of the 60 antibody-positive children who had a monophasic course, 23 were persistently positive, 34 seroconverted, and 3 had fluctuating serology.

Eventually, 54 children received an MS diagnosis. Of these, 83% were antibody negative at baseline. Ten children received a diagnosis of a relapsing non-MS demyelinating disorder; of these, 91% were antibody positive at baseline.

Dr. Fadda disclosed relationships with Atara Biotherapeutic and Sanofi-Genzyme.

[email protected]

SOURCE: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.

BERLIN – In children with an incident acquired demyelinating episode, the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) weighs against an eventual diagnosis of multiple sclerosis, especially if the child is younger than 11 years.

“Anti-MOG antibodies are present in about 30% of children with acquired demyelinating syndromes,” Giulia Fadda, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “About 80% experience a monophasic disease course.”

The antibodies are found in almost all children who have a relapsing non-MS demyelinating disease, said Dr. Fadda, who is a postdoctoral research fellow at the University of Pennsylvania, Philadelphia. But when the antibodies are present in children with an MS diagnosis, they identify a very specific subset with atypical clinical and imaging features.

The large prospective Canadian Pediatric Demyelinating Disease Study provided the sample for the study she presented at ECTRIMS. Children are recruited into the study soon after a first demyelinating event, and they are followed clinically, serologically, and with regular brain MRI.


The cohort in Dr. Fadda’s study comprised 275 children who were a mean of about 11 years old at symptom onset. The mean clinical follow-up was 6.7 years; the mean serologic follow-up, 4 years, and the mean imaging follow-up, 3.5 years. The study examined 1,368 serum samples and 1,459 MRI scans.

Overall, 32% of the children were positive for anti-MOG antibodies. Positivity was not associated with sex, but children with antibodies were significantly younger than those without (7 vs. 12 years). In fact, 77% of anti-MOG–positive children were younger than 11 years; just 15% of older children were positive for the antibodies.

Anti-MOG positivity was also associated with certain clinical phenotypes. Among positive children, 40% presented with optic neuritis, 37% with acute disseminated encephalomyelitis, and 14% with transverse myelitis; the rest had other phenotypes. Optic neuritis was significantly less common among antibody-negative patients (22%), as was encephalomyelitis (17%). Transverse myelitis was significantly more common (31%).

The analysis of MRI scans was stratified according to age younger than 11 years and 11 years and older. “The first thing we noticed among the younger MOG-positive children is that they had a high number of lesions, which were more commonly ill-defined, diffuse, and bilateral,” Dr. Fadda said. “Almost all the brain areas were affected, with a slight preponderance of thalamic and juxtacortical lesions. Among the MOG-negative children, lesions were more often perpendicular to the major axis of the corpus callosum.”

Among the older MOG antibody–positive children, the diffuse pattern was rarer, and the lesions were frequently cerebellar. “But by far, the features that best differentiated positivity from negativity were black holes and enhancing lesions, which we saw in a high proportion of children without the antibodies” at 73% and 49%, respectively.

Over a mean imaging follow-up period of 4 years, lesions were more likely to resolve completely in antibody-positive children than in those without antibodies (50% vs. 21%). Serologically, children who were MOG-antibody negative at baseline were likely to stay that way, with 99% remaining seronegative. Positive children, on the other hand, were significantly more likely to change serologic status, with 56% turning negative and 8% serologically fluctuating over the follow-up period; only 36% remained persistently seropositive. Persistent positive status was significantly associated with younger age (7 vs. 9 years) and an optic neuritis presentation (62% vs. 27%).

Most children (81%) who were antibody positive at baseline experienced no relapses. Among the 16 children who did experience a clinical relapse, the mean time to a second event was about 1 year. Nine of these children stayed persistently positive, while five seroconverted and two had fluctuating status.

Of the 60 antibody-positive children who had a monophasic course, 23 were persistently positive, 34 seroconverted, and 3 had fluctuating serology.

Eventually, 54 children received an MS diagnosis. Of these, 83% were antibody negative at baseline. Ten children received a diagnosis of a relapsing non-MS demyelinating disorder; of these, 91% were antibody positive at baseline.

Dr. Fadda disclosed relationships with Atara Biotherapeutic and Sanofi-Genzyme.

[email protected]

SOURCE: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.

BERLIN – In children with an incident acquired demyelinating episode, the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) weighs against an eventual diagnosis of multiple sclerosis, especially if the child is younger than 11 years.

“Anti-MOG antibodies are present in about 30% of children with acquired demyelinating syndromes,” Giulia Fadda, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “About 80% experience a monophasic disease course.”

The antibodies are found in almost all children who have a relapsing non-MS demyelinating disease, said Dr. Fadda, who is a postdoctoral research fellow at the University of Pennsylvania, Philadelphia. But when the antibodies are present in children with an MS diagnosis, they identify a very specific subset with atypical clinical and imaging features.

The large prospective Canadian Pediatric Demyelinating Disease Study provided the sample for the study she presented at ECTRIMS. Children are recruited into the study soon after a first demyelinating event, and they are followed clinically, serologically, and with regular brain MRI.


The cohort in Dr. Fadda’s study comprised 275 children who were a mean of about 11 years old at symptom onset. The mean clinical follow-up was 6.7 years; the mean serologic follow-up, 4 years, and the mean imaging follow-up, 3.5 years. The study examined 1,368 serum samples and 1,459 MRI scans.

Overall, 32% of the children were positive for anti-MOG antibodies. Positivity was not associated with sex, but children with antibodies were significantly younger than those without (7 vs. 12 years). In fact, 77% of anti-MOG–positive children were younger than 11 years; just 15% of older children were positive for the antibodies.

Anti-MOG positivity was also associated with certain clinical phenotypes. Among positive children, 40% presented with optic neuritis, 37% with acute disseminated encephalomyelitis, and 14% with transverse myelitis; the rest had other phenotypes. Optic neuritis was significantly less common among antibody-negative patients (22%), as was encephalomyelitis (17%). Transverse myelitis was significantly more common (31%).

The analysis of MRI scans was stratified according to age younger than 11 years and 11 years and older. “The first thing we noticed among the younger MOG-positive children is that they had a high number of lesions, which were more commonly ill-defined, diffuse, and bilateral,” Dr. Fadda said. “Almost all the brain areas were affected, with a slight preponderance of thalamic and juxtacortical lesions. Among the MOG-negative children, lesions were more often perpendicular to the major axis of the corpus callosum.”

Among the older MOG antibody–positive children, the diffuse pattern was rarer, and the lesions were frequently cerebellar. “But by far, the features that best differentiated positivity from negativity were black holes and enhancing lesions, which we saw in a high proportion of children without the antibodies” at 73% and 49%, respectively.

Over a mean imaging follow-up period of 4 years, lesions were more likely to resolve completely in antibody-positive children than in those without antibodies (50% vs. 21%). Serologically, children who were MOG-antibody negative at baseline were likely to stay that way, with 99% remaining seronegative. Positive children, on the other hand, were significantly more likely to change serologic status, with 56% turning negative and 8% serologically fluctuating over the follow-up period; only 36% remained persistently seropositive. Persistent positive status was significantly associated with younger age (7 vs. 9 years) and an optic neuritis presentation (62% vs. 27%).

Most children (81%) who were antibody positive at baseline experienced no relapses. Among the 16 children who did experience a clinical relapse, the mean time to a second event was about 1 year. Nine of these children stayed persistently positive, while five seroconverted and two had fluctuating status.

Of the 60 antibody-positive children who had a monophasic course, 23 were persistently positive, 34 seroconverted, and 3 had fluctuating serology.

Eventually, 54 children received an MS diagnosis. Of these, 83% were antibody negative at baseline. Ten children received a diagnosis of a relapsing non-MS demyelinating disorder; of these, 91% were antibody positive at baseline.

Dr. Fadda disclosed relationships with Atara Biotherapeutic and Sanofi-Genzyme.

[email protected]

SOURCE: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.

BERLIN – Demyelinating diseases appear to disrupt white matter development in children, slowing the trajectory of brain growth to almost unmeasurable levels, based on results from a single-center comparison study of 213 individuals.

While children with multiple sclerosis (MS) showed the most severe slowing, even a single demyelinating event slowed white matter growth, Robert A. Brown, PhD, said at the annual congress of the European Committees for Treatment and Research in Multiple Sclerosis.

Dr. Brown of the Montreal Neurological Institute at McGill University, Montreal, employed a signal mass correction of consecutive brain MRIs enhanced with magnetization transfer. Magnetization transfer ratio (MTR) quantifies myelin more effectively than does other imaging enhancement modalities, Dr. Brown said.

“It labels the macromolecules of myelin and correlates almost perfectly with Luxol fast blue stain on histology,” he said. And by measuring myelin instead of whole-brain volume, MTR sidesteps the confounders of inflammation and edema. “When tissue swells, the water dilutes the myelin. MRI is really sensitive to density, so dilution with water lowers that signal.”

But MTR isn’t failsafe either, he said, especially in teens. “A cautionary note: In healthy adolescents, white matter MTR can actually decrease, not increase, not because they are losing myelin but because the axons in brain tissue are growing so fast that they outstrip the production of new myelin. So, we can get another dilution effect here, except that instead of water, axons are diluting the myelin. We have to take that into account when using MTR.”

A volume-corrected MTR calculates both mass and volume to give what Dr. Brown termed signal mass. “We have demonstrated previously that signal mass is about twice as powerful as volume change alone for measuring the differences [in brain volume] between adults with MS and healthy controls.”

The study he presented at ECTRIMS used this technique to examine the trajectory of white matter change in a cohort of children from the Canadian Pediatric Demyelinating Disease Study who were all scanned at the same site in the same center. He compared brain volume at baseline and 1 year in 102 children with a monophasic demyelinating disease, 87 with MS, and 24 healthy, age-matched controls.

The children with MS were a median of about 17 years old at baseline, while those with a monophasic event and healthy controls were a median of about 12 years old. Median follow-up was 1 year in the healthy controls, 2 years in the MS cohort, and 4 years in the monophasic group. The investigators adjusted their comparisons for sex, since both bioavailable testosterone and androgen-receptor activity correlate with decreased MTR in young men. This doesn’t mean, though, that testosterone decreases myelination. Rather, it’s postulated that testosterone increases axonal caliber, which would decrease the number of neurons in each imaging voxel and, thus, the MTR signal (J Neurosci. 2008 Sep 17;28[38]:9519-24).

In the volume-only assessment, white matter in healthy controls increased at a rate of about 0.5% per year. White matter growth was about 0.2% per year in children with monophasic demyelination, which was significantly lower than in healthy controls.

“The MS children had no white matter growth that we could measure,” with an annual change of about 0.01%, Dr. Brown said. “It looks like a failure of normal development and was significantly lower than what we saw in the children with a demyelination event.”

MTR showed the expected age-associated decreases, which were highest among those with MS: –0.8% per year in healthy controls, –0.6% per year in those with a monophasic event, and –0.9% per year in those with MS.

The signal mass change showed the whole picture, Dr. Brown said. Signal mass declined 0.3% per year in healthy controls, 0.5% per year in the monophasic group, and 0.9% per year in the MS group – a significantly worse trajectory than either the control subjects or those with a monophasic event.

“Signal mass puts it all together and gives us the total picture of tissue loss, with quite severe loss in children with MS. It seems as though both monophasic insult and pediatric-onset MS disrupt brain development.”

Dr. Brown has been a consultant for NeuroRx Research and Biogen.

[email protected]

SOURCE: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63.

BERLIN – Demyelinating diseases appear to disrupt white matter development in children, slowing the trajectory of brain growth to almost unmeasurable levels, based on results from a single-center comparison study of 213 individuals.

While children with multiple sclerosis (MS) showed the most severe slowing, even a single demyelinating event slowed white matter growth, Robert A. Brown, PhD, said at the annual congress of the European Committees for Treatment and Research in Multiple Sclerosis.

Dr. Brown of the Montreal Neurological Institute at McGill University, Montreal, employed a signal mass correction of consecutive brain MRIs enhanced with magnetization transfer. Magnetization transfer ratio (MTR) quantifies myelin more effectively than does other imaging enhancement modalities, Dr. Brown said.

“It labels the macromolecules of myelin and correlates almost perfectly with Luxol fast blue stain on histology,” he said. And by measuring myelin instead of whole-brain volume, MTR sidesteps the confounders of inflammation and edema. “When tissue swells, the water dilutes the myelin. MRI is really sensitive to density, so dilution with water lowers that signal.”

But MTR isn’t failsafe either, he said, especially in teens. “A cautionary note: In healthy adolescents, white matter MTR can actually decrease, not increase, not because they are losing myelin but because the axons in brain tissue are growing so fast that they outstrip the production of new myelin. So, we can get another dilution effect here, except that instead of water, axons are diluting the myelin. We have to take that into account when using MTR.”

A volume-corrected MTR calculates both mass and volume to give what Dr. Brown termed signal mass. “We have demonstrated previously that signal mass is about twice as powerful as volume change alone for measuring the differences [in brain volume] between adults with MS and healthy controls.”

The study he presented at ECTRIMS used this technique to examine the trajectory of white matter change in a cohort of children from the Canadian Pediatric Demyelinating Disease Study who were all scanned at the same site in the same center. He compared brain volume at baseline and 1 year in 102 children with a monophasic demyelinating disease, 87 with MS, and 24 healthy, age-matched controls.

The children with MS were a median of about 17 years old at baseline, while those with a monophasic event and healthy controls were a median of about 12 years old. Median follow-up was 1 year in the healthy controls, 2 years in the MS cohort, and 4 years in the monophasic group. The investigators adjusted their comparisons for sex, since both bioavailable testosterone and androgen-receptor activity correlate with decreased MTR in young men. This doesn’t mean, though, that testosterone decreases myelination. Rather, it’s postulated that testosterone increases axonal caliber, which would decrease the number of neurons in each imaging voxel and, thus, the MTR signal (J Neurosci. 2008 Sep 17;28[38]:9519-24).

In the volume-only assessment, white matter in healthy controls increased at a rate of about 0.5% per year. White matter growth was about 0.2% per year in children with monophasic demyelination, which was significantly lower than in healthy controls.

“The MS children had no white matter growth that we could measure,” with an annual change of about 0.01%, Dr. Brown said. “It looks like a failure of normal development and was significantly lower than what we saw in the children with a demyelination event.”

MTR showed the expected age-associated decreases, which were highest among those with MS: –0.8% per year in healthy controls, –0.6% per year in those with a monophasic event, and –0.9% per year in those with MS.

The signal mass change showed the whole picture, Dr. Brown said. Signal mass declined 0.3% per year in healthy controls, 0.5% per year in the monophasic group, and 0.9% per year in the MS group – a significantly worse trajectory than either the control subjects or those with a monophasic event.

“Signal mass puts it all together and gives us the total picture of tissue loss, with quite severe loss in children with MS. It seems as though both monophasic insult and pediatric-onset MS disrupt brain development.”

Dr. Brown has been a consultant for NeuroRx Research and Biogen.

[email protected]

SOURCE: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63.

BERLIN – Demyelinating diseases appear to disrupt white matter development in children, slowing the trajectory of brain growth to almost unmeasurable levels, based on results from a single-center comparison study of 213 individuals.

While children with multiple sclerosis (MS) showed the most severe slowing, even a single demyelinating event slowed white matter growth, Robert A. Brown, PhD, said at the annual congress of the European Committees for Treatment and Research in Multiple Sclerosis.

Dr. Brown of the Montreal Neurological Institute at McGill University, Montreal, employed a signal mass correction of consecutive brain MRIs enhanced with magnetization transfer. Magnetization transfer ratio (MTR) quantifies myelin more effectively than does other imaging enhancement modalities, Dr. Brown said.

“It labels the macromolecules of myelin and correlates almost perfectly with Luxol fast blue stain on histology,” he said. And by measuring myelin instead of whole-brain volume, MTR sidesteps the confounders of inflammation and edema. “When tissue swells, the water dilutes the myelin. MRI is really sensitive to density, so dilution with water lowers that signal.”

But MTR isn’t failsafe either, he said, especially in teens. “A cautionary note: In healthy adolescents, white matter MTR can actually decrease, not increase, not because they are losing myelin but because the axons in brain tissue are growing so fast that they outstrip the production of new myelin. So, we can get another dilution effect here, except that instead of water, axons are diluting the myelin. We have to take that into account when using MTR.”

A volume-corrected MTR calculates both mass and volume to give what Dr. Brown termed signal mass. “We have demonstrated previously that signal mass is about twice as powerful as volume change alone for measuring the differences [in brain volume] between adults with MS and healthy controls.”

The study he presented at ECTRIMS used this technique to examine the trajectory of white matter change in a cohort of children from the Canadian Pediatric Demyelinating Disease Study who were all scanned at the same site in the same center. He compared brain volume at baseline and 1 year in 102 children with a monophasic demyelinating disease, 87 with MS, and 24 healthy, age-matched controls.

The children with MS were a median of about 17 years old at baseline, while those with a monophasic event and healthy controls were a median of about 12 years old. Median follow-up was 1 year in the healthy controls, 2 years in the MS cohort, and 4 years in the monophasic group. The investigators adjusted their comparisons for sex, since both bioavailable testosterone and androgen-receptor activity correlate with decreased MTR in young men. This doesn’t mean, though, that testosterone decreases myelination. Rather, it’s postulated that testosterone increases axonal caliber, which would decrease the number of neurons in each imaging voxel and, thus, the MTR signal (J Neurosci. 2008 Sep 17;28[38]:9519-24).

In the volume-only assessment, white matter in healthy controls increased at a rate of about 0.5% per year. White matter growth was about 0.2% per year in children with monophasic demyelination, which was significantly lower than in healthy controls.

“The MS children had no white matter growth that we could measure,” with an annual change of about 0.01%, Dr. Brown said. “It looks like a failure of normal development and was significantly lower than what we saw in the children with a demyelination event.”

MTR showed the expected age-associated decreases, which were highest among those with MS: –0.8% per year in healthy controls, –0.6% per year in those with a monophasic event, and –0.9% per year in those with MS.

The signal mass change showed the whole picture, Dr. Brown said. Signal mass declined 0.3% per year in healthy controls, 0.5% per year in the monophasic group, and 0.9% per year in the MS group – a significantly worse trajectory than either the control subjects or those with a monophasic event.

“Signal mass puts it all together and gives us the total picture of tissue loss, with quite severe loss in children with MS. It seems as though both monophasic insult and pediatric-onset MS disrupt brain development.”

Dr. Brown has been a consultant for NeuroRx Research and Biogen.

[email protected]

SOURCE: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63.

BERLIN – Switching to alemtuzumab from fingolimod is associated with improved disease activity in patients with relapsing-remitting multiple sclerosis (RRMS), according to the results of a real-world study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Sara Freeman/MDedge News

Jessica Frau, MD, of the University of Cagliari (Italy) reported that a switch from fingolimod (Gilenya) to alemtuzumab (Lemtrada) in 77 patients treated at 11 Italian centers was able to “reduce dramatically disease activity in patients who did not respond to fingolimod.”

Dr. Frau reported: “When we compared in our cohort the last year of fingolimod with the first year after the first course of alemtuzumab, we found a significant decrease in the annualized relapse rate [ARR].” The ARRs were 0.60 for fingolimod and 0.20 after 1 year of alemtuzumab treatment.

“We found also a trend towards an improvement in the EDSS [Expanded Disability Status Scale] score (P = .23), and less evidence of disease activity on MRI, both in terms of new T2 lesions and gadolinium-enhancing (Gd+) lesions.”

The last MRI during fingolimod treatment showed new T2 and Gd+ enhancing lesions in 69.2% and 58.6% of patients, respectively. Corresponding figures for the first MRI during alemtuzumab treatment were 10.4% and 2.2% of patients.

The beneficial effects of switching to fingolimod in the Italian study “was not influenced by a shorter washout [period] or a low lymphocyte count when alemtuzumab was started,” Dr. Frau said. A shorter washout period has been hypothesized to account for recent accounts of disease flares seen when switching from fingolimod to alemtuzumab, she explained.


Indeed, Dr. Frau noted that there had been a few studies that reported MS disease reactivation soon after the switch to alemtuzumab was made, which could be because lymphocytes remain in the lymph nodes when alemtuzumab is administered, this means that potentially they could repopulate the central nervous system and reactivate the disease.

However, “when alemtuzumab is started after fingolimod it is not a risk factor for reactivation of the disease,” Dr. Frau said, based on the current study’s findings.

As expected, the frequency of relapses increased during the washout period after stopping fingolimod, going from 12.7% of patients with relapse in the first month, 18.2% at 2 months, and 22.2% at 3 months. The time to first relapse from the start of alemtuzumab treatment was 6 months for 2.9% of patients, 9 months for 10.5% of patients, and 1 year for 20.7% of patients.

Asked to comment on when the optimal time to switch from fingolimod to alemtuzumab might be, Dr. Frau said: “The optimal time could be 1 month when the lymphocyte count is not too low.” However, lymphocyte counts were not measured in the entire cohort, so “these data perhaps need to have more strength.”

The switch from natalizumab to alemtuzumab

Other data on switching to alemtuzumab, this time from natalizumab (Tysabri), in the ANSWERS MS study were presented by Paul Gallagher, MBChB, of Queen Elizabeth University Hospital, London, and the University of Glasgow (Scotland).

Sara Freeman/MDedge News

ANSWERS MS (Alemtuzumab after Natalizumab Switch in Evolving Rapidly Severe MS) is a retrospective, observational analysis of routinely collected data on the use of alemtuzumab by 13 centers the United Kingdom and Ireland. These centers have been collecting data since before alemtuzumab was licensed in 2014 for MS, Dr. Gallagher observed, with some centers having experience of making the switch for more than a decade.

SOURCE: Frau J et al. Mult Scler. 2018;24(S2):100-1, Abstract 265; Gallagher P et al. Mult Scler. 2018;24(S2):99-100, Abstract 264.

BERLIN – Switching to alemtuzumab from fingolimod is associated with improved disease activity in patients with relapsing-remitting multiple sclerosis (RRMS), according to the results of a real-world study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Sara Freeman/MDedge News

Jessica Frau, MD, of the University of Cagliari (Italy) reported that a switch from fingolimod (Gilenya) to alemtuzumab (Lemtrada) in 77 patients treated at 11 Italian centers was able to “reduce dramatically disease activity in patients who did not respond to fingolimod.”

Dr. Frau reported: “When we compared in our cohort the last year of fingolimod with the first year after the first course of alemtuzumab, we found a significant decrease in the annualized relapse rate [ARR].” The ARRs were 0.60 for fingolimod and 0.20 after 1 year of alemtuzumab treatment.

“We found also a trend towards an improvement in the EDSS [Expanded Disability Status Scale] score (P = .23), and less evidence of disease activity on MRI, both in terms of new T2 lesions and gadolinium-enhancing (Gd+) lesions.”

The last MRI during fingolimod treatment showed new T2 and Gd+ enhancing lesions in 69.2% and 58.6% of patients, respectively. Corresponding figures for the first MRI during alemtuzumab treatment were 10.4% and 2.2% of patients.

The beneficial effects of switching to fingolimod in the Italian study “was not influenced by a shorter washout [period] or a low lymphocyte count when alemtuzumab was started,” Dr. Frau said. A shorter washout period has been hypothesized to account for recent accounts of disease flares seen when switching from fingolimod to alemtuzumab, she explained.


Indeed, Dr. Frau noted that there had been a few studies that reported MS disease reactivation soon after the switch to alemtuzumab was made, which could be because lymphocytes remain in the lymph nodes when alemtuzumab is administered, this means that potentially they could repopulate the central nervous system and reactivate the disease.

However, “when alemtuzumab is started after fingolimod it is not a risk factor for reactivation of the disease,” Dr. Frau said, based on the current study’s findings.

As expected, the frequency of relapses increased during the washout period after stopping fingolimod, going from 12.7% of patients with relapse in the first month, 18.2% at 2 months, and 22.2% at 3 months. The time to first relapse from the start of alemtuzumab treatment was 6 months for 2.9% of patients, 9 months for 10.5% of patients, and 1 year for 20.7% of patients.

Asked to comment on when the optimal time to switch from fingolimod to alemtuzumab might be, Dr. Frau said: “The optimal time could be 1 month when the lymphocyte count is not too low.” However, lymphocyte counts were not measured in the entire cohort, so “these data perhaps need to have more strength.”

The switch from natalizumab to alemtuzumab

Other data on switching to alemtuzumab, this time from natalizumab (Tysabri), in the ANSWERS MS study were presented by Paul Gallagher, MBChB, of Queen Elizabeth University Hospital, London, and the University of Glasgow (Scotland).

Sara Freeman/MDedge News

ANSWERS MS (Alemtuzumab after Natalizumab Switch in Evolving Rapidly Severe MS) is a retrospective, observational analysis of routinely collected data on the use of alemtuzumab by 13 centers the United Kingdom and Ireland. These centers have been collecting data since before alemtuzumab was licensed in 2014 for MS, Dr. Gallagher observed, with some centers having experience of making the switch for more than a decade.

SOURCE: Frau J et al. Mult Scler. 2018;24(S2):100-1, Abstract 265; Gallagher P et al. Mult Scler. 2018;24(S2):99-100, Abstract 264.

BERLIN – Switching to alemtuzumab from fingolimod is associated with improved disease activity in patients with relapsing-remitting multiple sclerosis (RRMS), according to the results of a real-world study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Sara Freeman/MDedge News

Jessica Frau, MD, of the University of Cagliari (Italy) reported that a switch from fingolimod (Gilenya) to alemtuzumab (Lemtrada) in 77 patients treated at 11 Italian centers was able to “reduce dramatically disease activity in patients who did not respond to fingolimod.”

Dr. Frau reported: “When we compared in our cohort the last year of fingolimod with the first year after the first course of alemtuzumab, we found a significant decrease in the annualized relapse rate [ARR].” The ARRs were 0.60 for fingolimod and 0.20 after 1 year of alemtuzumab treatment.

“We found also a trend towards an improvement in the EDSS [Expanded Disability Status Scale] score (P = .23), and less evidence of disease activity on MRI, both in terms of new T2 lesions and gadolinium-enhancing (Gd+) lesions.”

The last MRI during fingolimod treatment showed new T2 and Gd+ enhancing lesions in 69.2% and 58.6% of patients, respectively. Corresponding figures for the first MRI during alemtuzumab treatment were 10.4% and 2.2% of patients.

The beneficial effects of switching to fingolimod in the Italian study “was not influenced by a shorter washout [period] or a low lymphocyte count when alemtuzumab was started,” Dr. Frau said. A shorter washout period has been hypothesized to account for recent accounts of disease flares seen when switching from fingolimod to alemtuzumab, she explained.


Indeed, Dr. Frau noted that there had been a few studies that reported MS disease reactivation soon after the switch to alemtuzumab was made, which could be because lymphocytes remain in the lymph nodes when alemtuzumab is administered, this means that potentially they could repopulate the central nervous system and reactivate the disease.

However, “when alemtuzumab is started after fingolimod it is not a risk factor for reactivation of the disease,” Dr. Frau said, based on the current study’s findings.

As expected, the frequency of relapses increased during the washout period after stopping fingolimod, going from 12.7% of patients with relapse in the first month, 18.2% at 2 months, and 22.2% at 3 months. The time to first relapse from the start of alemtuzumab treatment was 6 months for 2.9% of patients, 9 months for 10.5% of patients, and 1 year for 20.7% of patients.

Asked to comment on when the optimal time to switch from fingolimod to alemtuzumab might be, Dr. Frau said: “The optimal time could be 1 month when the lymphocyte count is not too low.” However, lymphocyte counts were not measured in the entire cohort, so “these data perhaps need to have more strength.”

The switch from natalizumab to alemtuzumab

Other data on switching to alemtuzumab, this time from natalizumab (Tysabri), in the ANSWERS MS study were presented by Paul Gallagher, MBChB, of Queen Elizabeth University Hospital, London, and the University of Glasgow (Scotland).

Sara Freeman/MDedge News

ANSWERS MS (Alemtuzumab after Natalizumab Switch in Evolving Rapidly Severe MS) is a retrospective, observational analysis of routinely collected data on the use of alemtuzumab by 13 centers the United Kingdom and Ireland. These centers have been collecting data since before alemtuzumab was licensed in 2014 for MS, Dr. Gallagher observed, with some centers having experience of making the switch for more than a decade.

SOURCE: Frau J et al. Mult Scler. 2018;24(S2):100-1, Abstract 265; Gallagher P et al. Mult Scler. 2018;24(S2):99-100, Abstract 264.

BERLIN—Higher vitamin D levels at multiple sclerosis (MS) onset predict higher cognitive function 11 years later, according to research presented at ECTRIMS 2018. People who are heavy smokers at MS onset have a clinically significant decline in cognitive function at 11 years, according to the researchers.

“Higher vitamin D in the first years after clinically isolated syndrome (CIS) was associated with better cognitive function and lower neuronal injury at Year 11,” said Marianna Cortese, MD, a research fellow at the Harvard T.H. Chan School of Public Health in Boston. “Vitamin D supplementation during the early years with the disease might be neuroprotective.”

The BENEFIT-11 Trial

According to Dr. Cortese, 40% to 70% of patients with MS experience cognitive decline during their disease course. There is no specific treatment for cognitive decline.

Smoking, low levels of vitamin D, and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS and have been associated with more active MS and progressive disease. Whether these factors predict cognitive status had not been known, said Dr. Cortese.

Investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.

The observational study followed 278 participants with CIS in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled study of interferon beta-1b for the early treatment of CIS. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.

“To minimize reverse causation, we used exposure status in the first two years after CIS to predict progression outcomes at Year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline and at study Months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used to indicate EBV seropositivity.

The cognitive performance measure used in the study was the Paced Auditory Serial Addition Test (PASAT), a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study Years 1, 2, 5, and 11. At study Year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.

In multivariable analysis, the researchers adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease on baseline MRI, BMI, and whether the patient was treated with steroids during CIS.

Vitamin D Protected Against Neuroaxonal Injury

“Higher quintiles of mean vitamin D levels during the first two years were associated with lower odds of scoring worse on the PASAT at Year 11,” said Dr. Cortese. The significant trend across the quintiles suggests a dose–response relationship, she said. Dr. Cortese explained that “scoring worse” meant scoring below the median.

A 50-nmol/L increase in mean 25(OH)D in study Months 6 through 24 predicted 65% lower odds of having a PASAT score below the median at Year 11. “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.

Cotinine levels obtained during the first two years were used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker. If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the nine patients who were heavy smokers, as indicated by cotinine levels over 189 ng/mL.

“Smokers, compared to nonsmokers, had a significantly lower standardized PASAT score at Year 11,” said Dr. Cortese. “Heavy smokers had an up to 0.6-standard deviation-lower PASAT score at Year 11.... This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.” Early smoking had a dose–response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients,” said Dr. Cortese.

Epstein-Barr antibodies were not associated with cognitive function at Year 11.

“The findings of neuroaxonal injury at Year 11 using serum neurofilament light chain measures corroborated the main findings on cognitive function at Year 11,” said Dr. Cortese. A 50-nmol increase in vitamin D level within the first five years was associated with 20% lower neurofilament light chain levels at Year 11, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first five years had neurofilament light chain levels that were 20% higher than those of other participants. “They had more neuroaxonal loss,” said Dr. Cortese. Neurofilament light chain levels at Year 11 were not associated with early EBV status, she said.

Radiologic and other clinical data from BENEFIT-11 are also being studied and will be reported in the future, said Dr. Cortese.

Dr. Cortese reported no conflicts of interest. Several coauthors reported financial relationships with pharmaceutical companies. The study was supported by the NIH and the National MS Society, with clinical support from Bayer HealthCare.

—Kari Oakes

BERLIN—Higher vitamin D levels at multiple sclerosis (MS) onset predict higher cognitive function 11 years later, according to research presented at ECTRIMS 2018. People who are heavy smokers at MS onset have a clinically significant decline in cognitive function at 11 years, according to the researchers.

“Higher vitamin D in the first years after clinically isolated syndrome (CIS) was associated with better cognitive function and lower neuronal injury at Year 11,” said Marianna Cortese, MD, a research fellow at the Harvard T.H. Chan School of Public Health in Boston. “Vitamin D supplementation during the early years with the disease might be neuroprotective.”

The BENEFIT-11 Trial

According to Dr. Cortese, 40% to 70% of patients with MS experience cognitive decline during their disease course. There is no specific treatment for cognitive decline.

Smoking, low levels of vitamin D, and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS and have been associated with more active MS and progressive disease. Whether these factors predict cognitive status had not been known, said Dr. Cortese.

Investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.

The observational study followed 278 participants with CIS in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled study of interferon beta-1b for the early treatment of CIS. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.

“To minimize reverse causation, we used exposure status in the first two years after CIS to predict progression outcomes at Year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline and at study Months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used to indicate EBV seropositivity.

The cognitive performance measure used in the study was the Paced Auditory Serial Addition Test (PASAT), a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study Years 1, 2, 5, and 11. At study Year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.

In multivariable analysis, the researchers adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease on baseline MRI, BMI, and whether the patient was treated with steroids during CIS.

Vitamin D Protected Against Neuroaxonal Injury

“Higher quintiles of mean vitamin D levels during the first two years were associated with lower odds of scoring worse on the PASAT at Year 11,” said Dr. Cortese. The significant trend across the quintiles suggests a dose–response relationship, she said. Dr. Cortese explained that “scoring worse” meant scoring below the median.

A 50-nmol/L increase in mean 25(OH)D in study Months 6 through 24 predicted 65% lower odds of having a PASAT score below the median at Year 11. “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.

Cotinine levels obtained during the first two years were used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker. If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the nine patients who were heavy smokers, as indicated by cotinine levels over 189 ng/mL.

“Smokers, compared to nonsmokers, had a significantly lower standardized PASAT score at Year 11,” said Dr. Cortese. “Heavy smokers had an up to 0.6-standard deviation-lower PASAT score at Year 11.... This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.” Early smoking had a dose–response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients,” said Dr. Cortese.

Epstein-Barr antibodies were not associated with cognitive function at Year 11.

“The findings of neuroaxonal injury at Year 11 using serum neurofilament light chain measures corroborated the main findings on cognitive function at Year 11,” said Dr. Cortese. A 50-nmol increase in vitamin D level within the first five years was associated with 20% lower neurofilament light chain levels at Year 11, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first five years had neurofilament light chain levels that were 20% higher than those of other participants. “They had more neuroaxonal loss,” said Dr. Cortese. Neurofilament light chain levels at Year 11 were not associated with early EBV status, she said.

Radiologic and other clinical data from BENEFIT-11 are also being studied and will be reported in the future, said Dr. Cortese.

Dr. Cortese reported no conflicts of interest. Several coauthors reported financial relationships with pharmaceutical companies. The study was supported by the NIH and the National MS Society, with clinical support from Bayer HealthCare.

—Kari Oakes

BERLIN—Higher vitamin D levels at multiple sclerosis (MS) onset predict higher cognitive function 11 years later, according to research presented at ECTRIMS 2018. People who are heavy smokers at MS onset have a clinically significant decline in cognitive function at 11 years, according to the researchers.

“Higher vitamin D in the first years after clinically isolated syndrome (CIS) was associated with better cognitive function and lower neuronal injury at Year 11,” said Marianna Cortese, MD, a research fellow at the Harvard T.H. Chan School of Public Health in Boston. “Vitamin D supplementation during the early years with the disease might be neuroprotective.”

The BENEFIT-11 Trial

According to Dr. Cortese, 40% to 70% of patients with MS experience cognitive decline during their disease course. There is no specific treatment for cognitive decline.

Smoking, low levels of vitamin D, and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS and have been associated with more active MS and progressive disease. Whether these factors predict cognitive status had not been known, said Dr. Cortese.

Investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.

The observational study followed 278 participants with CIS in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled study of interferon beta-1b for the early treatment of CIS. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.

“To minimize reverse causation, we used exposure status in the first two years after CIS to predict progression outcomes at Year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline and at study Months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used to indicate EBV seropositivity.

The cognitive performance measure used in the study was the Paced Auditory Serial Addition Test (PASAT), a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study Years 1, 2, 5, and 11. At study Year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.

In multivariable analysis, the researchers adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease on baseline MRI, BMI, and whether the patient was treated with steroids during CIS.

Vitamin D Protected Against Neuroaxonal Injury

“Higher quintiles of mean vitamin D levels during the first two years were associated with lower odds of scoring worse on the PASAT at Year 11,” said Dr. Cortese. The significant trend across the quintiles suggests a dose–response relationship, she said. Dr. Cortese explained that “scoring worse” meant scoring below the median.

A 50-nmol/L increase in mean 25(OH)D in study Months 6 through 24 predicted 65% lower odds of having a PASAT score below the median at Year 11. “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.

Cotinine levels obtained during the first two years were used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker. If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the nine patients who were heavy smokers, as indicated by cotinine levels over 189 ng/mL.

“Smokers, compared to nonsmokers, had a significantly lower standardized PASAT score at Year 11,” said Dr. Cortese. “Heavy smokers had an up to 0.6-standard deviation-lower PASAT score at Year 11.... This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.” Early smoking had a dose–response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients,” said Dr. Cortese.

Epstein-Barr antibodies were not associated with cognitive function at Year 11.

“The findings of neuroaxonal injury at Year 11 using serum neurofilament light chain measures corroborated the main findings on cognitive function at Year 11,” said Dr. Cortese. A 50-nmol increase in vitamin D level within the first five years was associated with 20% lower neurofilament light chain levels at Year 11, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first five years had neurofilament light chain levels that were 20% higher than those of other participants. “They had more neuroaxonal loss,” said Dr. Cortese. Neurofilament light chain levels at Year 11 were not associated with early EBV status, she said.

Radiologic and other clinical data from BENEFIT-11 are also being studied and will be reported in the future, said Dr. Cortese.

Dr. Cortese reported no conflicts of interest. Several coauthors reported financial relationships with pharmaceutical companies. The study was supported by the NIH and the National MS Society, with clinical support from Bayer HealthCare.

—Kari Oakes

BERLIN—Relapse-induced escalation to a highly effective disease-modifying therapy (DMT) is associated with a reduced risk of relapses, according to comprehensive nationwide data from Danish patients with multiple sclerosis (MS). Escalation is associated with a statistically nonsignificant trend toward reduced time to first one-point worsening of Expanded Disability Status Scale (EDSS) score over the short-to-medium term. “Escalation of therapy to a highly effective DMT when patients experience relapses on a moderately effective DMT is recommended to improve control of relapse activity,” said Thor Ameri Chalmer, MD, a doctoral student at Rigshospitalet in Copenhagen, and colleagues at ECTRIMS 2018.

Patients with relapsing-remitting MS who have relapses often switch to a new DMT. Treatment guidelines recommend switching to a highly effective DMT when a patient experiences clinical disease breakthrough. Nevertheless, patients may switch between moderately effective DMTs because of breakthrough disease or adverse effects. Dr. Chalmer and colleagues compared treatment effectiveness between highly effective DMTs and moderately effective DMTs in patients with relapsing-remitting MS who switch therapy because of relapse activity.

In this registry-based cohort study, the investigators retrieved data from the Danish MS Registry on all adults with relapsing-remitting MS. Eligible participants had an EDSS score below 6, experienced a relapse while treated with a moderately effective DMT, and consequently switched to a highly effective DMT or another moderately effective DMT. The groups were compared from treatment initiation until outcome or censoring. Censoring was defined as postbaseline switch between highly effective DMT and moderately effective DMT, cessation of therapy, relocation, or death, whichever occurred first. The primary outcomes were annualized relapse rate (ARR), relapse rate ratio, time to first relapse, and time to first one-point confirmed EDSS worsening. Dr. Chalmer and colleagues used propensity score matching to balance groups, a Cox proportional hazards model to obtain hazard ratios (HR) when modeling time to first relapse and time to first worsening, and negative binomial regression to obtain ARR and relapse rate ratios.

The matched cohort included 814 patients (407 in each group). The median follow-up time was 3.2 years. The group of patients who switched to a highly effective DMT had a 39% lower hazard rate of reaching first relapse (HR, 0.61). ARRs were 0.21 for patients who switched to a highly effective DMT and 0.34 for patients who switched to a moderately effective DMT. Relapse rate ratio for highly effective DMT compared with moderately effective DMT was 0.62. The group who switched to a highly effective DMT had 13% lower hazard rate of one-point EDSS worsening (HR, 0.87).

BERLIN—Relapse-induced escalation to a highly effective disease-modifying therapy (DMT) is associated with a reduced risk of relapses, according to comprehensive nationwide data from Danish patients with multiple sclerosis (MS). Escalation is associated with a statistically nonsignificant trend toward reduced time to first one-point worsening of Expanded Disability Status Scale (EDSS) score over the short-to-medium term. “Escalation of therapy to a highly effective DMT when patients experience relapses on a moderately effective DMT is recommended to improve control of relapse activity,” said Thor Ameri Chalmer, MD, a doctoral student at Rigshospitalet in Copenhagen, and colleagues at ECTRIMS 2018.

Patients with relapsing-remitting MS who have relapses often switch to a new DMT. Treatment guidelines recommend switching to a highly effective DMT when a patient experiences clinical disease breakthrough. Nevertheless, patients may switch between moderately effective DMTs because of breakthrough disease or adverse effects. Dr. Chalmer and colleagues compared treatment effectiveness between highly effective DMTs and moderately effective DMTs in patients with relapsing-remitting MS who switch therapy because of relapse activity.

In this registry-based cohort study, the investigators retrieved data from the Danish MS Registry on all adults with relapsing-remitting MS. Eligible participants had an EDSS score below 6, experienced a relapse while treated with a moderately effective DMT, and consequently switched to a highly effective DMT or another moderately effective DMT. The groups were compared from treatment initiation until outcome or censoring. Censoring was defined as postbaseline switch between highly effective DMT and moderately effective DMT, cessation of therapy, relocation, or death, whichever occurred first. The primary outcomes were annualized relapse rate (ARR), relapse rate ratio, time to first relapse, and time to first one-point confirmed EDSS worsening. Dr. Chalmer and colleagues used propensity score matching to balance groups, a Cox proportional hazards model to obtain hazard ratios (HR) when modeling time to first relapse and time to first worsening, and negative binomial regression to obtain ARR and relapse rate ratios.

The matched cohort included 814 patients (407 in each group). The median follow-up time was 3.2 years. The group of patients who switched to a highly effective DMT had a 39% lower hazard rate of reaching first relapse (HR, 0.61). ARRs were 0.21 for patients who switched to a highly effective DMT and 0.34 for patients who switched to a moderately effective DMT. Relapse rate ratio for highly effective DMT compared with moderately effective DMT was 0.62. The group who switched to a highly effective DMT had 13% lower hazard rate of one-point EDSS worsening (HR, 0.87).

BERLIN—Relapse-induced escalation to a highly effective disease-modifying therapy (DMT) is associated with a reduced risk of relapses, according to comprehensive nationwide data from Danish patients with multiple sclerosis (MS). Escalation is associated with a statistically nonsignificant trend toward reduced time to first one-point worsening of Expanded Disability Status Scale (EDSS) score over the short-to-medium term. “Escalation of therapy to a highly effective DMT when patients experience relapses on a moderately effective DMT is recommended to improve control of relapse activity,” said Thor Ameri Chalmer, MD, a doctoral student at Rigshospitalet in Copenhagen, and colleagues at ECTRIMS 2018.

Patients with relapsing-remitting MS who have relapses often switch to a new DMT. Treatment guidelines recommend switching to a highly effective DMT when a patient experiences clinical disease breakthrough. Nevertheless, patients may switch between moderately effective DMTs because of breakthrough disease or adverse effects. Dr. Chalmer and colleagues compared treatment effectiveness between highly effective DMTs and moderately effective DMTs in patients with relapsing-remitting MS who switch therapy because of relapse activity.

In this registry-based cohort study, the investigators retrieved data from the Danish MS Registry on all adults with relapsing-remitting MS. Eligible participants had an EDSS score below 6, experienced a relapse while treated with a moderately effective DMT, and consequently switched to a highly effective DMT or another moderately effective DMT. The groups were compared from treatment initiation until outcome or censoring. Censoring was defined as postbaseline switch between highly effective DMT and moderately effective DMT, cessation of therapy, relocation, or death, whichever occurred first. The primary outcomes were annualized relapse rate (ARR), relapse rate ratio, time to first relapse, and time to first one-point confirmed EDSS worsening. Dr. Chalmer and colleagues used propensity score matching to balance groups, a Cox proportional hazards model to obtain hazard ratios (HR) when modeling time to first relapse and time to first worsening, and negative binomial regression to obtain ARR and relapse rate ratios.

The matched cohort included 814 patients (407 in each group). The median follow-up time was 3.2 years. The group of patients who switched to a highly effective DMT had a 39% lower hazard rate of reaching first relapse (HR, 0.61). ARRs were 0.21 for patients who switched to a highly effective DMT and 0.34 for patients who switched to a moderately effective DMT. Relapse rate ratio for highly effective DMT compared with moderately effective DMT was 0.62. The group who switched to a highly effective DMT had 13% lower hazard rate of one-point EDSS worsening (HR, 0.87).

BERLIN—Spinal cord volume deficits in patients with multiple sclerosis (MS) may explain clinical disability that appears out of proportion to lesion load on brain imaging, according to research presented at ECTRIMS 2018.

In a pool of 362 patients with mild to moderate MS-related disability and identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes, compared with those with mild disability.

An Analysis of Patient Records

Some patients with MS have a relatively high level of disability, but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in patients with MS and a pronounced dissociation between intracerebral lesion load and disability, said Michaela Andelova, MD, of Charles University in Prague.

Dr. Andelova and her colleagues hypothesized that spinal cord volume would differ between patients with varying levels of disability despite identical white matter lesion load. To test this hypothesis, they looked at records for 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability and extent of cerebral T2 hyperintense lesion load. The investigators identified 53 patients whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5. They called them the low lesion load–high disability (LLHD) group.

The researchers then identified another 71 patients with a volume of T2-weighted hyperintensities greater than 9 mL, but whose EDSS score was less than 1.5. They called them the high lesion load–low disability (HLLD) group.

The remaining 1,121 patients, who did not have these paradoxical associations, were analyzed separately.The investigators measured mean upper cervical cord area (MUCCA) for all patients. On the basis of images acquired by a 3-T MRI scanner, they used an in-house, semiautomated method to calculate MUCCA as the mean sum of spinal cord area in 21 slices centered at the C3–C4 intervertebral disk.

Mean Upper Cervical Cord Area Correlated With Disability

“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of the thalamus and callosum, and smaller lateral ventricles than the HLLD group,” said Dr. Andelova and her collaborators.

However, the LLHD patients had MUCCA values that were significantly lower than those of the other groups. The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. The difference between these groups was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller than that of the other groups, at 80.40 mm2.

Next, Dr. Andelova and her colleagues compared 362 patients with moderate disability (ie, EDSS scores between 3.5 and 6.5) with matched patients who had mild MS-related disability (ie, EDSS score less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the group with moderate disability (78.86 mm2 vs 84.44 mm2).

In addition to having identical lesion loads, the mild and moderate disability groups had similar normalized total brain volume and regional brain volumes. The group with moderate disability had slightly less white matter volume, said Dr. Andelova. All differences between groups retained statistical significance after adjustment for potential confounders such as age, sex, and duration of disease.

“Reduced spinal cord volume may explain part of the clinical–radiologic paradox in patients who have high disability despite low intracranial lesion load,” said the researchers. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”

Dr. Andelova and her collaborators plan to examine cerebral lesion distribution and perform quantitative MRI investigations of lesion distribution. They intend to seek potential associations between various distribution patterns and accelerated spinal atrophy.

—Kari Oakes 

BERLIN—Spinal cord volume deficits in patients with multiple sclerosis (MS) may explain clinical disability that appears out of proportion to lesion load on brain imaging, according to research presented at ECTRIMS 2018.

In a pool of 362 patients with mild to moderate MS-related disability and identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes, compared with those with mild disability.

An Analysis of Patient Records

Some patients with MS have a relatively high level of disability, but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in patients with MS and a pronounced dissociation between intracerebral lesion load and disability, said Michaela Andelova, MD, of Charles University in Prague.

Dr. Andelova and her colleagues hypothesized that spinal cord volume would differ between patients with varying levels of disability despite identical white matter lesion load. To test this hypothesis, they looked at records for 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability and extent of cerebral T2 hyperintense lesion load. The investigators identified 53 patients whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5. They called them the low lesion load–high disability (LLHD) group.

The researchers then identified another 71 patients with a volume of T2-weighted hyperintensities greater than 9 mL, but whose EDSS score was less than 1.5. They called them the high lesion load–low disability (HLLD) group.

The remaining 1,121 patients, who did not have these paradoxical associations, were analyzed separately.The investigators measured mean upper cervical cord area (MUCCA) for all patients. On the basis of images acquired by a 3-T MRI scanner, they used an in-house, semiautomated method to calculate MUCCA as the mean sum of spinal cord area in 21 slices centered at the C3–C4 intervertebral disk.

Mean Upper Cervical Cord Area Correlated With Disability

“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of the thalamus and callosum, and smaller lateral ventricles than the HLLD group,” said Dr. Andelova and her collaborators.

However, the LLHD patients had MUCCA values that were significantly lower than those of the other groups. The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. The difference between these groups was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller than that of the other groups, at 80.40 mm2.

Next, Dr. Andelova and her colleagues compared 362 patients with moderate disability (ie, EDSS scores between 3.5 and 6.5) with matched patients who had mild MS-related disability (ie, EDSS score less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the group with moderate disability (78.86 mm2 vs 84.44 mm2).

In addition to having identical lesion loads, the mild and moderate disability groups had similar normalized total brain volume and regional brain volumes. The group with moderate disability had slightly less white matter volume, said Dr. Andelova. All differences between groups retained statistical significance after adjustment for potential confounders such as age, sex, and duration of disease.

“Reduced spinal cord volume may explain part of the clinical–radiologic paradox in patients who have high disability despite low intracranial lesion load,” said the researchers. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”

Dr. Andelova and her collaborators plan to examine cerebral lesion distribution and perform quantitative MRI investigations of lesion distribution. They intend to seek potential associations between various distribution patterns and accelerated spinal atrophy.

—Kari Oakes 

BERLIN—Spinal cord volume deficits in patients with multiple sclerosis (MS) may explain clinical disability that appears out of proportion to lesion load on brain imaging, according to research presented at ECTRIMS 2018.

In a pool of 362 patients with mild to moderate MS-related disability and identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes, compared with those with mild disability.

An Analysis of Patient Records

Some patients with MS have a relatively high level of disability, but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in patients with MS and a pronounced dissociation between intracerebral lesion load and disability, said Michaela Andelova, MD, of Charles University in Prague.

Dr. Andelova and her colleagues hypothesized that spinal cord volume would differ between patients with varying levels of disability despite identical white matter lesion load. To test this hypothesis, they looked at records for 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability and extent of cerebral T2 hyperintense lesion load. The investigators identified 53 patients whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5. They called them the low lesion load–high disability (LLHD) group.

The researchers then identified another 71 patients with a volume of T2-weighted hyperintensities greater than 9 mL, but whose EDSS score was less than 1.5. They called them the high lesion load–low disability (HLLD) group.

The remaining 1,121 patients, who did not have these paradoxical associations, were analyzed separately.The investigators measured mean upper cervical cord area (MUCCA) for all patients. On the basis of images acquired by a 3-T MRI scanner, they used an in-house, semiautomated method to calculate MUCCA as the mean sum of spinal cord area in 21 slices centered at the C3–C4 intervertebral disk.

Mean Upper Cervical Cord Area Correlated With Disability

“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of the thalamus and callosum, and smaller lateral ventricles than the HLLD group,” said Dr. Andelova and her collaborators.

However, the LLHD patients had MUCCA values that were significantly lower than those of the other groups. The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. The difference between these groups was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller than that of the other groups, at 80.40 mm2.

Next, Dr. Andelova and her colleagues compared 362 patients with moderate disability (ie, EDSS scores between 3.5 and 6.5) with matched patients who had mild MS-related disability (ie, EDSS score less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the group with moderate disability (78.86 mm2 vs 84.44 mm2).

In addition to having identical lesion loads, the mild and moderate disability groups had similar normalized total brain volume and regional brain volumes. The group with moderate disability had slightly less white matter volume, said Dr. Andelova. All differences between groups retained statistical significance after adjustment for potential confounders such as age, sex, and duration of disease.

“Reduced spinal cord volume may explain part of the clinical–radiologic paradox in patients who have high disability despite low intracranial lesion load,” said the researchers. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”

Dr. Andelova and her collaborators plan to examine cerebral lesion distribution and perform quantitative MRI investigations of lesion distribution. They intend to seek potential associations between various distribution patterns and accelerated spinal atrophy.

—Kari Oakes