ICYMI Multiple Sclerosis

Patients with MS and migraine have a greater number of relapses and cognitive symptoms than MS patients without migraine and experience a “markedly more symptomatic MS course.”

SEATTLE—Patients with multiple sclerosis (MS) reported a threefold increase in migraine frequency compared with age- and gender-matched controls, according to findings presented at the 61st Annual Meeting of the American Academy of Neurology.

Ilya Kister, MD, Assistant Professor at New York University (NYU) School of Medicine in New York City, and colleagues distributed questionnaires to 225 patients in the waiting room of the NYU MS Center. Ninety percent (n = 204) completed the survey. Results were analyzed to compare migraine rates in MS patients with those of matched historical controls from the American Migraine Prevalence and Prevention (AMPP) study. The researchers also compared symptom profiles and severity of MS in patients with migraine and those with no headache, assessed for possible associations between migraine and other conditions in patients with MS, and compared brain MRI characteristics in MS patients with and without migraine.

Frequency and Characteristics of Migraine in MS Patients
According to Dr. Kister and colleagues, the overall headache frequency was in the range reported in previous studies of headache in MS patients. Sixty-four percent of patients (n = 131) reported “a headache within the past year not related to trauma, infection, or medication.” Of these, 94 (72%) met International Classification of Headache Disorders, Second Edition criteria for migraine; the remaining 37 (28%) met criteria for tension-type headaches.

The one-year prevalence of migraine among patients with MS was threefold greater than that of the general population (AMPP cohort), both for men (18.4% vs 5.6%) and women (55.7% vs 17.1%). Thirty-six percent of MS patients with migraine reported aura. The frequency of migraine with aura and distribution of aura types was similar to that of patients with migraine in the AMPP study.

Migraine severity, which was determined using the Migraine Disability Assessment Scale (MIDAS), did not differ between the MS and AMPP cohorts. Seventy-seven percent of MS patients with migraine and 75% of AMPP subjects with migraine had mild to moderate disability (MIDAS grades 1 and 2), while the remainder had frequent and severe migraine disability (MIDAS grades 3 and 4).

MS Relapses, Painful and Nonpainful Symptoms, and MRI Characteristics
MS patients with migraine self-reported more relapses than did those without migraine. Among MS patients with migraine, 28% reported three or more relapses during the past year and 20% had none. In contrast, among MS patients without headache, 10% had three or more relapses during the past year, and 32% had none. More MS patients without headache had no relapses compared with MS patients with migraine.

Pain-related symptoms, such as Lhermitte’s sign, occipital and trigeminal neuralgia, facial pain, temporomandibular joint-related pain, spasms, and restless legs syndrome, were 2.5 times more common in MS patients with migraine than in those without headache. Twenty-six percent of patients with migraine reported frequent, non–headache-related allodynia. In addition, more than 20% of migraineurs reported using analgesics for nonheadache reasons, compared with 7% of headache-free patients.

Dr. Kister and colleagues also found that MS patients with migraine reported more cognitive, psychiatric, brainstem, and visual symptoms and scored higher on depression and anxiety scales (Patient Health Questionnaire–9), the Fatigue Severity Scale, and the Epworth Sleepiness Scale. No differences were observed in self-reported ambulation scores, hours of sleep per night, and overall quality of life.

Brain MRI scans were available for 138 of the 204 MS patients (67%), including 50 migraineurs and 65 headache-free patients. No differences were observed in the number and distribution of T2 hyperintense lesions or the number of gadolinium-enhancing lesions between the two groups; however, there were more T1 hypointense lesions in the headache-free group.

Recommendations
Because migraines are common and often disabling, Dr. Kister’s team recommended that a headache history be elicited from all MS patients, “as [migraine] is often overshadowed by other MS symptoms and yet can be effectively treated in many cases.”

The researchers concluded that “population-based, prospective studies with objective documentation of relapses and disability, and controlled for interferon-1b use, are necessary to definitively establish an association between MS and migraines, to clarify the nature of the association (unidirectional vs bidirectional), and to confirm our findings that MS migraineurs experience a markedly more symptomatic MS course.”   

Patients with MS and migraine have a greater number of relapses and cognitive symptoms than MS patients without migraine and experience a “markedly more symptomatic MS course.”

SEATTLE—Patients with multiple sclerosis (MS) reported a threefold increase in migraine frequency compared with age- and gender-matched controls, according to findings presented at the 61st Annual Meeting of the American Academy of Neurology.

Ilya Kister, MD, Assistant Professor at New York University (NYU) School of Medicine in New York City, and colleagues distributed questionnaires to 225 patients in the waiting room of the NYU MS Center. Ninety percent (n = 204) completed the survey. Results were analyzed to compare migraine rates in MS patients with those of matched historical controls from the American Migraine Prevalence and Prevention (AMPP) study. The researchers also compared symptom profiles and severity of MS in patients with migraine and those with no headache, assessed for possible associations between migraine and other conditions in patients with MS, and compared brain MRI characteristics in MS patients with and without migraine.

Frequency and Characteristics of Migraine in MS Patients
According to Dr. Kister and colleagues, the overall headache frequency was in the range reported in previous studies of headache in MS patients. Sixty-four percent of patients (n = 131) reported “a headache within the past year not related to trauma, infection, or medication.” Of these, 94 (72%) met International Classification of Headache Disorders, Second Edition criteria for migraine; the remaining 37 (28%) met criteria for tension-type headaches.

The one-year prevalence of migraine among patients with MS was threefold greater than that of the general population (AMPP cohort), both for men (18.4% vs 5.6%) and women (55.7% vs 17.1%). Thirty-six percent of MS patients with migraine reported aura. The frequency of migraine with aura and distribution of aura types was similar to that of patients with migraine in the AMPP study.

Migraine severity, which was determined using the Migraine Disability Assessment Scale (MIDAS), did not differ between the MS and AMPP cohorts. Seventy-seven percent of MS patients with migraine and 75% of AMPP subjects with migraine had mild to moderate disability (MIDAS grades 1 and 2), while the remainder had frequent and severe migraine disability (MIDAS grades 3 and 4).

MS Relapses, Painful and Nonpainful Symptoms, and MRI Characteristics
MS patients with migraine self-reported more relapses than did those without migraine. Among MS patients with migraine, 28% reported three or more relapses during the past year and 20% had none. In contrast, among MS patients without headache, 10% had three or more relapses during the past year, and 32% had none. More MS patients without headache had no relapses compared with MS patients with migraine.

Pain-related symptoms, such as Lhermitte’s sign, occipital and trigeminal neuralgia, facial pain, temporomandibular joint-related pain, spasms, and restless legs syndrome, were 2.5 times more common in MS patients with migraine than in those without headache. Twenty-six percent of patients with migraine reported frequent, non–headache-related allodynia. In addition, more than 20% of migraineurs reported using analgesics for nonheadache reasons, compared with 7% of headache-free patients.

Dr. Kister and colleagues also found that MS patients with migraine reported more cognitive, psychiatric, brainstem, and visual symptoms and scored higher on depression and anxiety scales (Patient Health Questionnaire–9), the Fatigue Severity Scale, and the Epworth Sleepiness Scale. No differences were observed in self-reported ambulation scores, hours of sleep per night, and overall quality of life.

Brain MRI scans were available for 138 of the 204 MS patients (67%), including 50 migraineurs and 65 headache-free patients. No differences were observed in the number and distribution of T2 hyperintense lesions or the number of gadolinium-enhancing lesions between the two groups; however, there were more T1 hypointense lesions in the headache-free group.

Recommendations
Because migraines are common and often disabling, Dr. Kister’s team recommended that a headache history be elicited from all MS patients, “as [migraine] is often overshadowed by other MS symptoms and yet can be effectively treated in many cases.”

The researchers concluded that “population-based, prospective studies with objective documentation of relapses and disability, and controlled for interferon-1b use, are necessary to definitively establish an association between MS and migraines, to clarify the nature of the association (unidirectional vs bidirectional), and to confirm our findings that MS migraineurs experience a markedly more symptomatic MS course.”   

Patients with MS and migraine have a greater number of relapses and cognitive symptoms than MS patients without migraine and experience a “markedly more symptomatic MS course.”

SEATTLE—Patients with multiple sclerosis (MS) reported a threefold increase in migraine frequency compared with age- and gender-matched controls, according to findings presented at the 61st Annual Meeting of the American Academy of Neurology.

Ilya Kister, MD, Assistant Professor at New York University (NYU) School of Medicine in New York City, and colleagues distributed questionnaires to 225 patients in the waiting room of the NYU MS Center. Ninety percent (n = 204) completed the survey. Results were analyzed to compare migraine rates in MS patients with those of matched historical controls from the American Migraine Prevalence and Prevention (AMPP) study. The researchers also compared symptom profiles and severity of MS in patients with migraine and those with no headache, assessed for possible associations between migraine and other conditions in patients with MS, and compared brain MRI characteristics in MS patients with and without migraine.

Frequency and Characteristics of Migraine in MS Patients
According to Dr. Kister and colleagues, the overall headache frequency was in the range reported in previous studies of headache in MS patients. Sixty-four percent of patients (n = 131) reported “a headache within the past year not related to trauma, infection, or medication.” Of these, 94 (72%) met International Classification of Headache Disorders, Second Edition criteria for migraine; the remaining 37 (28%) met criteria for tension-type headaches.

The one-year prevalence of migraine among patients with MS was threefold greater than that of the general population (AMPP cohort), both for men (18.4% vs 5.6%) and women (55.7% vs 17.1%). Thirty-six percent of MS patients with migraine reported aura. The frequency of migraine with aura and distribution of aura types was similar to that of patients with migraine in the AMPP study.

Migraine severity, which was determined using the Migraine Disability Assessment Scale (MIDAS), did not differ between the MS and AMPP cohorts. Seventy-seven percent of MS patients with migraine and 75% of AMPP subjects with migraine had mild to moderate disability (MIDAS grades 1 and 2), while the remainder had frequent and severe migraine disability (MIDAS grades 3 and 4).

MS Relapses, Painful and Nonpainful Symptoms, and MRI Characteristics
MS patients with migraine self-reported more relapses than did those without migraine. Among MS patients with migraine, 28% reported three or more relapses during the past year and 20% had none. In contrast, among MS patients without headache, 10% had three or more relapses during the past year, and 32% had none. More MS patients without headache had no relapses compared with MS patients with migraine.

Pain-related symptoms, such as Lhermitte’s sign, occipital and trigeminal neuralgia, facial pain, temporomandibular joint-related pain, spasms, and restless legs syndrome, were 2.5 times more common in MS patients with migraine than in those without headache. Twenty-six percent of patients with migraine reported frequent, non–headache-related allodynia. In addition, more than 20% of migraineurs reported using analgesics for nonheadache reasons, compared with 7% of headache-free patients.

Dr. Kister and colleagues also found that MS patients with migraine reported more cognitive, psychiatric, brainstem, and visual symptoms and scored higher on depression and anxiety scales (Patient Health Questionnaire–9), the Fatigue Severity Scale, and the Epworth Sleepiness Scale. No differences were observed in self-reported ambulation scores, hours of sleep per night, and overall quality of life.

Brain MRI scans were available for 138 of the 204 MS patients (67%), including 50 migraineurs and 65 headache-free patients. No differences were observed in the number and distribution of T2 hyperintense lesions or the number of gadolinium-enhancing lesions between the two groups; however, there were more T1 hypointense lesions in the headache-free group.

Recommendations
Because migraines are common and often disabling, Dr. Kister’s team recommended that a headache history be elicited from all MS patients, “as [migraine] is often overshadowed by other MS symptoms and yet can be effectively treated in many cases.”

The researchers concluded that “population-based, prospective studies with objective documentation of relapses and disability, and controlled for interferon-1b use, are necessary to definitively establish an association between MS and migraines, to clarify the nature of the association (unidirectional vs bidirectional), and to confirm our findings that MS migraineurs experience a markedly more symptomatic MS course.”   

ATLANTA—Increasing evidence supports an association between vitamin D deficiency and multiple sclerosis (MS), as researchers have found that high supplemental doses of the vitamin are safe and significantly reduced relapse rates in patients with the disease.

Among patients who received a mean of 14,000 IU/day of vitamin D3—which is more than three times the daily amount recommended by the FDA for many adults and included doses as high as 40,000 IU/day—16% had a relapse, compared with 38% of controls who had taken an average of 1,000 IU/day, reported Jodie Burton, MD, a neurologist at St. Michael’s Hospital, University of Toronto, and colleagues at the 23rd Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

Potential environmental and genetic causes have been a recent focus of MS research. Studies have shown that a higher incidence of MS occurs in regions where sunlight is not as prevalent and that vitamin D levels and ultraviolet radiation exposure early in life may have an impact on the risk of MS.

“If you are unfortunate enough to live at either pole, you basically don’t have sufficient ultraviolet radiation/sun exposure to produce much vitamin D,” said Dr. Burton. “If you live in North America, you have roughly six months or less of ultraviolet radiation to produce a reasonable amount of vitamin D. Closer to the equator, you have the bulk of the year getting good ultraviolet radiation exposure and the potential for vitamin D sufficiency.”

Vitamin D is produced naturally in the skin when ultraviolet radiation is absorbed and is then converted to 25-hydroxyvitamin D [25(OH)D] and the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D] form. Serum concentration of 25(OH)D is regarded as the most reliable indicator of vitamin D status.

Some investigators have hypothesized that vitamin D may act as an immune modulator in decreasing proliferation of proinflammatory T leukocytes and in decreasing production of various cytokines. “We know MS is predominantly an immune-mediated disease, so presumably vitamin D would have to act on the immune system to be biologically valid,” said Dr. Burton.

If Effective, What Is an Appropriate Dose?

The current recommended daily dose of vitamin D is based on the amount believed to prevent rickets in children, “which is great when you are worried about getting rickets, and which is not so great when you are trying to accomplish something else,” said Dr. Burton. “So if you are looking for compelling evidence that that amount of vitamin D has any impact on the immune system, you are not going to find any.” The FDA recommends 200 IU/day for those up to age 50, 400 IU/day for those 51 to 70, and 600 IU/day for those older than 70. “The amounts are pretty low,” said Dr. Burton.

Dr. Burton and colleagues sought to determine whether vitamin D could have a positive impact on patients already diagnosed with MS and what a safe and effective dose would be. The randomized controlled trial included 25 patients on an escalating dose regimen of vitamin D3 and 24 control subjects who took an average of 1,000 IU/day. The dose of vitamin D was escalated for six months to 40,000 IU/day and then was de-escalated down to zero, for a mean of 14,000 IU/day, with about 70% of the year spent at 10,000 IU/day or higher. All participants also received 1,200 mg/day of calcium throughout the trial.

Calcium was used for two reasons, noted Dr. Burton. “People take calcium regularly, so we wanted to make sure you could add vitamin D to calcium without consequences,” she said. “Second, in studies with the animal model of MS—experimental autoimmune encephalitis—as well as cancer prevention studies, vitamin D and calcium appear to work synergistically.”

The primary outcome measures were those of safety, and included mean change in serum calcium in the treatment group for each dose change and mean difference in serum calcium treatment compared with controls. Secondary outcomes were efficacy related and included changes within and between patient groups for relapse activity, Expanded Disability Status Scale (EDSS) score, and ambulation index. A total of 23 treatment patients completed the trial, along with 22 controls. Patients were seen about every six weeks in the treatment group and at four time points in the control group.

Safety and Efficacy of High-Dose Vitamin D

Dr. Burton and colleagues found that serum calcium levels remained steady and within normal limits throughout the dosing regimen, and there were no significant differences between treated patients and control patients at any time point. Mean urine calcium/creatinine levels in the treatment group were also well within normal, increasing slightly at the higher dosing levels, which is to be expected, according to Dr. Burton.

However, serum 25(OH)D levels increased with high vitamin D doses. At 40,000 IU/day, the mean 25(OH)D level approached 420 nmol/L, “which would scare most people,” said Dr. Burton, adding that 250 nmol/L is the “so-called” normal acceptable level of toxicity. “Despite these values, nobody had any calcium-related consequences whatsoever. So it makes you question exactly how you define toxicity.”

Among clinical outcomes, the treatment group did significantly better, achieving a 41% reduction in annualized relapse rate, compared with a reduction rate of 17% in the control group. “This is with the caveat that this was not blinded, so the result has to be taken with a grain of salt,” commented Dr. Burton.

However, the researchers found a significant change when comparing disability status at time of study entry to disability status at the end of the trial. About 8% of the treatment group left the trial with a greater EDSS score than when they started, versus 37.5% in the control group. “The caveat is that these were small changes in EDSS, so again the clinical interpretation is open to debate, but certainly this was a very robust outcome.”

Regarding immunologic changes, the treatment group compared with the control group, and participants with 25(OH)D levels of 100 nmol/L or greater had a significant drop in their T-cell reactivity and proliferation, a finding not observed in patients who had taken lower doses of vitamin D.

Dr. Burton offered some other reasons as to why patients with MS have low levels of 25(OH)D, including that they may intentionally avoid sun exposure, they do not engage in enough physical activity, and they use steroids. The only adverse event was mild constipation in four treatment patients, and with a change or discontinuation in the calcium supplement, all had resolution of this symptom. One patient had a benign breast calcification on mammography, but the lesion was later found to have been present before the trial.

“We believe that vitamin D3 intake up to 40,000 IU/day for a brief period of time and 10,000q IU/day for a year appears to demonstrate biochemical safety, evidence of clinical benefit, with a grain of salt, and evidence of decreased T-cell proliferation,” Dr. Burton concluded.

Vitamin D Deficiency Linked to MS Severity

In a second trial presented at the 2009 CMSC, researchers found that vitamin D deficiency was associated with a higher disability score and a faster rate of disease progression in patients with MS.

Allison Drake, Neurology-Psychology Research Coordinator, University at Buffalo, State University of New York, and colleagues included 349 patients with MS from the New York State Multiple Sclerosis Consortium in their retrospective study. They used the EDSS to measure disability and the MS Severity Scale (MSSS) to measure the rate of disease progression. Patients also completed a questionnaire regarding clinical and demographic data and provided a blood sample.

A majority of patients were female and Caucasian, the average age was about 50, and most had relapsing-remitting MS. Levels of vitamin D greater than 32 ng/mL were regarded as sufficient, levels between 20 and 32 were insufficient, and levels less than 20 were deficient. About 37% of participants had sufficient levels of vitamin D, 41% had insufficient levels, and 22% had deficient levels.

Due to seasonal changes in exposure to ultraviolet radiation that occur in Buffalo, the researchers examined fluctuations in mean vitamin D levels collected during different seasons and by disease severity. As expected, vitamin D levels were highest during seasons when sun exposure was at its peak, between July and September. On average, less than sufficient levels were detected in all patients during all other seasons. “Interestingly, patients with severe disability, as noted by EDSS scores greater than 6, did not reach sufficient levels at any time during any month,” said Ms. Drake.

In an ordinal regression analysis, after controlling for age, gender, age of disease onset, season, and MS subtype, the researchers found that serum vitamin D levels were significantly predictive of EDSS score. “Patients who were vitamin D deficient were more likely to have high EDSS scores and high disability,” said Ms. Drake. “Also significant were non–relapsing-remitting diagnoses and increasing age. Logistic regression revealed that patients who were vitamin D deficient were 3.3 times more likely to be severely disabled with EDSS scores of greater than 6, compared with patients who had sufficient levels.”

Linear regression analysis also demonstrated that vitamin D levels and MS disease subtype significantly predicted MSSS score. “Though it wasn’t the strongest predictor, decreasing vitamin D levels did make a statistically significant contribution,” said Ms. Drake.

“The results of this study demonstrate that serum vitamin D levels are associated with MS-related disability and disease severity assessed by the EDSS and MSSS,” concluded Ms. Drake. “Patients with deficient vitamin D levels are more likely to have higher EDSS scores, showing more disability, and to have higher MSSS scores, showing more rapid rate of progression. These [findings] can be interpreted in that vitamin D levels in patients with MS may have a potentially protective role if they are sufficient or they may have a detrimental effect if they are deficient.”

—Colby Stong

ATLANTA—Increasing evidence supports an association between vitamin D deficiency and multiple sclerosis (MS), as researchers have found that high supplemental doses of the vitamin are safe and significantly reduced relapse rates in patients with the disease.

Among patients who received a mean of 14,000 IU/day of vitamin D3—which is more than three times the daily amount recommended by the FDA for many adults and included doses as high as 40,000 IU/day—16% had a relapse, compared with 38% of controls who had taken an average of 1,000 IU/day, reported Jodie Burton, MD, a neurologist at St. Michael’s Hospital, University of Toronto, and colleagues at the 23rd Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

Potential environmental and genetic causes have been a recent focus of MS research. Studies have shown that a higher incidence of MS occurs in regions where sunlight is not as prevalent and that vitamin D levels and ultraviolet radiation exposure early in life may have an impact on the risk of MS.

“If you are unfortunate enough to live at either pole, you basically don’t have sufficient ultraviolet radiation/sun exposure to produce much vitamin D,” said Dr. Burton. “If you live in North America, you have roughly six months or less of ultraviolet radiation to produce a reasonable amount of vitamin D. Closer to the equator, you have the bulk of the year getting good ultraviolet radiation exposure and the potential for vitamin D sufficiency.”

Vitamin D is produced naturally in the skin when ultraviolet radiation is absorbed and is then converted to 25-hydroxyvitamin D [25(OH)D] and the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D] form. Serum concentration of 25(OH)D is regarded as the most reliable indicator of vitamin D status.

Some investigators have hypothesized that vitamin D may act as an immune modulator in decreasing proliferation of proinflammatory T leukocytes and in decreasing production of various cytokines. “We know MS is predominantly an immune-mediated disease, so presumably vitamin D would have to act on the immune system to be biologically valid,” said Dr. Burton.

If Effective, What Is an Appropriate Dose?

The current recommended daily dose of vitamin D is based on the amount believed to prevent rickets in children, “which is great when you are worried about getting rickets, and which is not so great when you are trying to accomplish something else,” said Dr. Burton. “So if you are looking for compelling evidence that that amount of vitamin D has any impact on the immune system, you are not going to find any.” The FDA recommends 200 IU/day for those up to age 50, 400 IU/day for those 51 to 70, and 600 IU/day for those older than 70. “The amounts are pretty low,” said Dr. Burton.

Dr. Burton and colleagues sought to determine whether vitamin D could have a positive impact on patients already diagnosed with MS and what a safe and effective dose would be. The randomized controlled trial included 25 patients on an escalating dose regimen of vitamin D3 and 24 control subjects who took an average of 1,000 IU/day. The dose of vitamin D was escalated for six months to 40,000 IU/day and then was de-escalated down to zero, for a mean of 14,000 IU/day, with about 70% of the year spent at 10,000 IU/day or higher. All participants also received 1,200 mg/day of calcium throughout the trial.

Calcium was used for two reasons, noted Dr. Burton. “People take calcium regularly, so we wanted to make sure you could add vitamin D to calcium without consequences,” she said. “Second, in studies with the animal model of MS—experimental autoimmune encephalitis—as well as cancer prevention studies, vitamin D and calcium appear to work synergistically.”

The primary outcome measures were those of safety, and included mean change in serum calcium in the treatment group for each dose change and mean difference in serum calcium treatment compared with controls. Secondary outcomes were efficacy related and included changes within and between patient groups for relapse activity, Expanded Disability Status Scale (EDSS) score, and ambulation index. A total of 23 treatment patients completed the trial, along with 22 controls. Patients were seen about every six weeks in the treatment group and at four time points in the control group.

Safety and Efficacy of High-Dose Vitamin D

Dr. Burton and colleagues found that serum calcium levels remained steady and within normal limits throughout the dosing regimen, and there were no significant differences between treated patients and control patients at any time point. Mean urine calcium/creatinine levels in the treatment group were also well within normal, increasing slightly at the higher dosing levels, which is to be expected, according to Dr. Burton.

However, serum 25(OH)D levels increased with high vitamin D doses. At 40,000 IU/day, the mean 25(OH)D level approached 420 nmol/L, “which would scare most people,” said Dr. Burton, adding that 250 nmol/L is the “so-called” normal acceptable level of toxicity. “Despite these values, nobody had any calcium-related consequences whatsoever. So it makes you question exactly how you define toxicity.”

Among clinical outcomes, the treatment group did significantly better, achieving a 41% reduction in annualized relapse rate, compared with a reduction rate of 17% in the control group. “This is with the caveat that this was not blinded, so the result has to be taken with a grain of salt,” commented Dr. Burton.

However, the researchers found a significant change when comparing disability status at time of study entry to disability status at the end of the trial. About 8% of the treatment group left the trial with a greater EDSS score than when they started, versus 37.5% in the control group. “The caveat is that these were small changes in EDSS, so again the clinical interpretation is open to debate, but certainly this was a very robust outcome.”

Regarding immunologic changes, the treatment group compared with the control group, and participants with 25(OH)D levels of 100 nmol/L or greater had a significant drop in their T-cell reactivity and proliferation, a finding not observed in patients who had taken lower doses of vitamin D.

Dr. Burton offered some other reasons as to why patients with MS have low levels of 25(OH)D, including that they may intentionally avoid sun exposure, they do not engage in enough physical activity, and they use steroids. The only adverse event was mild constipation in four treatment patients, and with a change or discontinuation in the calcium supplement, all had resolution of this symptom. One patient had a benign breast calcification on mammography, but the lesion was later found to have been present before the trial.

“We believe that vitamin D3 intake up to 40,000 IU/day for a brief period of time and 10,000q IU/day for a year appears to demonstrate biochemical safety, evidence of clinical benefit, with a grain of salt, and evidence of decreased T-cell proliferation,” Dr. Burton concluded.

Vitamin D Deficiency Linked to MS Severity

In a second trial presented at the 2009 CMSC, researchers found that vitamin D deficiency was associated with a higher disability score and a faster rate of disease progression in patients with MS.

Allison Drake, Neurology-Psychology Research Coordinator, University at Buffalo, State University of New York, and colleagues included 349 patients with MS from the New York State Multiple Sclerosis Consortium in their retrospective study. They used the EDSS to measure disability and the MS Severity Scale (MSSS) to measure the rate of disease progression. Patients also completed a questionnaire regarding clinical and demographic data and provided a blood sample.

A majority of patients were female and Caucasian, the average age was about 50, and most had relapsing-remitting MS. Levels of vitamin D greater than 32 ng/mL were regarded as sufficient, levels between 20 and 32 were insufficient, and levels less than 20 were deficient. About 37% of participants had sufficient levels of vitamin D, 41% had insufficient levels, and 22% had deficient levels.

Due to seasonal changes in exposure to ultraviolet radiation that occur in Buffalo, the researchers examined fluctuations in mean vitamin D levels collected during different seasons and by disease severity. As expected, vitamin D levels were highest during seasons when sun exposure was at its peak, between July and September. On average, less than sufficient levels were detected in all patients during all other seasons. “Interestingly, patients with severe disability, as noted by EDSS scores greater than 6, did not reach sufficient levels at any time during any month,” said Ms. Drake.

In an ordinal regression analysis, after controlling for age, gender, age of disease onset, season, and MS subtype, the researchers found that serum vitamin D levels were significantly predictive of EDSS score. “Patients who were vitamin D deficient were more likely to have high EDSS scores and high disability,” said Ms. Drake. “Also significant were non–relapsing-remitting diagnoses and increasing age. Logistic regression revealed that patients who were vitamin D deficient were 3.3 times more likely to be severely disabled with EDSS scores of greater than 6, compared with patients who had sufficient levels.”

Linear regression analysis also demonstrated that vitamin D levels and MS disease subtype significantly predicted MSSS score. “Though it wasn’t the strongest predictor, decreasing vitamin D levels did make a statistically significant contribution,” said Ms. Drake.

“The results of this study demonstrate that serum vitamin D levels are associated with MS-related disability and disease severity assessed by the EDSS and MSSS,” concluded Ms. Drake. “Patients with deficient vitamin D levels are more likely to have higher EDSS scores, showing more disability, and to have higher MSSS scores, showing more rapid rate of progression. These [findings] can be interpreted in that vitamin D levels in patients with MS may have a potentially protective role if they are sufficient or they may have a detrimental effect if they are deficient.”

—Colby Stong

ATLANTA—Increasing evidence supports an association between vitamin D deficiency and multiple sclerosis (MS), as researchers have found that high supplemental doses of the vitamin are safe and significantly reduced relapse rates in patients with the disease.

Among patients who received a mean of 14,000 IU/day of vitamin D3—which is more than three times the daily amount recommended by the FDA for many adults and included doses as high as 40,000 IU/day—16% had a relapse, compared with 38% of controls who had taken an average of 1,000 IU/day, reported Jodie Burton, MD, a neurologist at St. Michael’s Hospital, University of Toronto, and colleagues at the 23rd Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

Potential environmental and genetic causes have been a recent focus of MS research. Studies have shown that a higher incidence of MS occurs in regions where sunlight is not as prevalent and that vitamin D levels and ultraviolet radiation exposure early in life may have an impact on the risk of MS.

“If you are unfortunate enough to live at either pole, you basically don’t have sufficient ultraviolet radiation/sun exposure to produce much vitamin D,” said Dr. Burton. “If you live in North America, you have roughly six months or less of ultraviolet radiation to produce a reasonable amount of vitamin D. Closer to the equator, you have the bulk of the year getting good ultraviolet radiation exposure and the potential for vitamin D sufficiency.”

Vitamin D is produced naturally in the skin when ultraviolet radiation is absorbed and is then converted to 25-hydroxyvitamin D [25(OH)D] and the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D] form. Serum concentration of 25(OH)D is regarded as the most reliable indicator of vitamin D status.

Some investigators have hypothesized that vitamin D may act as an immune modulator in decreasing proliferation of proinflammatory T leukocytes and in decreasing production of various cytokines. “We know MS is predominantly an immune-mediated disease, so presumably vitamin D would have to act on the immune system to be biologically valid,” said Dr. Burton.

If Effective, What Is an Appropriate Dose?

The current recommended daily dose of vitamin D is based on the amount believed to prevent rickets in children, “which is great when you are worried about getting rickets, and which is not so great when you are trying to accomplish something else,” said Dr. Burton. “So if you are looking for compelling evidence that that amount of vitamin D has any impact on the immune system, you are not going to find any.” The FDA recommends 200 IU/day for those up to age 50, 400 IU/day for those 51 to 70, and 600 IU/day for those older than 70. “The amounts are pretty low,” said Dr. Burton.

Dr. Burton and colleagues sought to determine whether vitamin D could have a positive impact on patients already diagnosed with MS and what a safe and effective dose would be. The randomized controlled trial included 25 patients on an escalating dose regimen of vitamin D3 and 24 control subjects who took an average of 1,000 IU/day. The dose of vitamin D was escalated for six months to 40,000 IU/day and then was de-escalated down to zero, for a mean of 14,000 IU/day, with about 70% of the year spent at 10,000 IU/day or higher. All participants also received 1,200 mg/day of calcium throughout the trial.

Calcium was used for two reasons, noted Dr. Burton. “People take calcium regularly, so we wanted to make sure you could add vitamin D to calcium without consequences,” she said. “Second, in studies with the animal model of MS—experimental autoimmune encephalitis—as well as cancer prevention studies, vitamin D and calcium appear to work synergistically.”

The primary outcome measures were those of safety, and included mean change in serum calcium in the treatment group for each dose change and mean difference in serum calcium treatment compared with controls. Secondary outcomes were efficacy related and included changes within and between patient groups for relapse activity, Expanded Disability Status Scale (EDSS) score, and ambulation index. A total of 23 treatment patients completed the trial, along with 22 controls. Patients were seen about every six weeks in the treatment group and at four time points in the control group.

Safety and Efficacy of High-Dose Vitamin D

Dr. Burton and colleagues found that serum calcium levels remained steady and within normal limits throughout the dosing regimen, and there were no significant differences between treated patients and control patients at any time point. Mean urine calcium/creatinine levels in the treatment group were also well within normal, increasing slightly at the higher dosing levels, which is to be expected, according to Dr. Burton.

However, serum 25(OH)D levels increased with high vitamin D doses. At 40,000 IU/day, the mean 25(OH)D level approached 420 nmol/L, “which would scare most people,” said Dr. Burton, adding that 250 nmol/L is the “so-called” normal acceptable level of toxicity. “Despite these values, nobody had any calcium-related consequences whatsoever. So it makes you question exactly how you define toxicity.”

Among clinical outcomes, the treatment group did significantly better, achieving a 41% reduction in annualized relapse rate, compared with a reduction rate of 17% in the control group. “This is with the caveat that this was not blinded, so the result has to be taken with a grain of salt,” commented Dr. Burton.

However, the researchers found a significant change when comparing disability status at time of study entry to disability status at the end of the trial. About 8% of the treatment group left the trial with a greater EDSS score than when they started, versus 37.5% in the control group. “The caveat is that these were small changes in EDSS, so again the clinical interpretation is open to debate, but certainly this was a very robust outcome.”

Regarding immunologic changes, the treatment group compared with the control group, and participants with 25(OH)D levels of 100 nmol/L or greater had a significant drop in their T-cell reactivity and proliferation, a finding not observed in patients who had taken lower doses of vitamin D.

Dr. Burton offered some other reasons as to why patients with MS have low levels of 25(OH)D, including that they may intentionally avoid sun exposure, they do not engage in enough physical activity, and they use steroids. The only adverse event was mild constipation in four treatment patients, and with a change or discontinuation in the calcium supplement, all had resolution of this symptom. One patient had a benign breast calcification on mammography, but the lesion was later found to have been present before the trial.

“We believe that vitamin D3 intake up to 40,000 IU/day for a brief period of time and 10,000q IU/day for a year appears to demonstrate biochemical safety, evidence of clinical benefit, with a grain of salt, and evidence of decreased T-cell proliferation,” Dr. Burton concluded.

Vitamin D Deficiency Linked to MS Severity

In a second trial presented at the 2009 CMSC, researchers found that vitamin D deficiency was associated with a higher disability score and a faster rate of disease progression in patients with MS.

Allison Drake, Neurology-Psychology Research Coordinator, University at Buffalo, State University of New York, and colleagues included 349 patients with MS from the New York State Multiple Sclerosis Consortium in their retrospective study. They used the EDSS to measure disability and the MS Severity Scale (MSSS) to measure the rate of disease progression. Patients also completed a questionnaire regarding clinical and demographic data and provided a blood sample.

A majority of patients were female and Caucasian, the average age was about 50, and most had relapsing-remitting MS. Levels of vitamin D greater than 32 ng/mL were regarded as sufficient, levels between 20 and 32 were insufficient, and levels less than 20 were deficient. About 37% of participants had sufficient levels of vitamin D, 41% had insufficient levels, and 22% had deficient levels.

Due to seasonal changes in exposure to ultraviolet radiation that occur in Buffalo, the researchers examined fluctuations in mean vitamin D levels collected during different seasons and by disease severity. As expected, vitamin D levels were highest during seasons when sun exposure was at its peak, between July and September. On average, less than sufficient levels were detected in all patients during all other seasons. “Interestingly, patients with severe disability, as noted by EDSS scores greater than 6, did not reach sufficient levels at any time during any month,” said Ms. Drake.

In an ordinal regression analysis, after controlling for age, gender, age of disease onset, season, and MS subtype, the researchers found that serum vitamin D levels were significantly predictive of EDSS score. “Patients who were vitamin D deficient were more likely to have high EDSS scores and high disability,” said Ms. Drake. “Also significant were non–relapsing-remitting diagnoses and increasing age. Logistic regression revealed that patients who were vitamin D deficient were 3.3 times more likely to be severely disabled with EDSS scores of greater than 6, compared with patients who had sufficient levels.”

Linear regression analysis also demonstrated that vitamin D levels and MS disease subtype significantly predicted MSSS score. “Though it wasn’t the strongest predictor, decreasing vitamin D levels did make a statistically significant contribution,” said Ms. Drake.

“The results of this study demonstrate that serum vitamin D levels are associated with MS-related disability and disease severity assessed by the EDSS and MSSS,” concluded Ms. Drake. “Patients with deficient vitamin D levels are more likely to have higher EDSS scores, showing more disability, and to have higher MSSS scores, showing more rapid rate of progression. These [findings] can be interpreted in that vitamin D levels in patients with MS may have a potentially protective role if they are sufficient or they may have a detrimental effect if they are deficient.”

—Colby Stong

SEATTLE—Women with multiple sclerosis (MS) may be able to reduce their risk for postpartum relapses by breastfeeding, according to findings that were presented at the 61st Annual Meeting of the American Academy of Neurology.

Previous studies have shown that breastfeeding may offer only limited protection against postpartum relapses in women with MS; however, these studies did not account for early supplemental infant formula feedings. Therefore, researchers from Stanford University and Northern California Kaiser Permanente Health Care System were interested in determining the effect of exclusive breastfeeding on risk of postpartum MS relapses, compared with not breastfeeding or breastfeeding combined with supplemental infant formula feedings.

“We prospectively followed 32 pregnant women with MS and 29 age-matched, pregnant controls and conducted structured interviews to assess clinical, menstrual, and breastfeeding history during each trimester and two, four, six, nine, and 12 months postpartum,” said Annette Langer-Gould, MD, a research scientist and neurologist at Kaiser Permanente Southern California. Patients were enrolled between 2002 and 2005.

Exclusive breastfeeding was defined as at least one bottle of breast milk per day, without regular supplemental infant formula feedings, for at least two months postpartum. “We chose the two-month cutoff, because we wanted it to be something that women could realistically achieve,” said Dr. Langer-Gould.

Exclusive Breastfeeding Appears to Be Protective
The researchers found that “fewer women with MS breastfed at all, compared to their healthy matched controls.” Fifty-two percent of women with MS did not breastfeed exclusively or began regular supplemental infant formula feedings within two months postpartum; of these, 87% had a postpartum relapse. In comparison, 36% of women who breastfed exclusively for at least two months postpartum had a relapse—in most cases, much later than women who did not breastfeed exclusively.

Seventy-three percent of women who decided to forego breastfeeding stated that they did so to resume MS therapies. Dr. Langer-Gould noted that more women who did not exclusively breastfeed had used immunomodulatory therapies in the year prior to becoming pregnant and might have had more frequent relapses prior to becoming pregnant as well, compared with women who breastfed exclusively. However, the effect of exclusive breastfeeding was still highly protective even after taking these factors into account.

Women who resumed MS therapies and did not breastfeed exclusively within the first two months postpartum had a significantly higher risk of postpartum relapses than women with MS who did not restart medications, regardless of breastfeeding status, noted Dr. Langer-Gould. These findings are interesting, she said, particularly because “our data certainly show that there is a belief that pregnant women with more severe disease should resume medications instead of breastfeeding after giving birth.”

Dr. Langer-Gould hypothesized that anovulation may play a role in protecting against postpartum relapse. Experimental autoimmune encephalitis models have shown that all states of anovulation appear to be protective against relapse, potentially explaining why pregnant women and women who exclusively breastfeed might show protection against relapse, she said. She noted that women who breastfed exclusively in the current study had a later return of menses.

Weighing the Risks and Benefits of Resuming Medications
“Our findings call into question the benefit of choosing not to breastfeed or stopping breastfeeding early to start taking MS therapies,” stated Dr. Langer-Gould. “Our study found no evidence that breastfeeding is harmful or that resuming MS medications is helpful in preventing postpartum relapses. Larger studies need to be done to establish whether breastfeeding exclusively is actually better than resuming medications.

“Future studies should also establish the safety of these medications during lactation, as has been done for antidepressants, which is a different concern than safety during pregnancy. That way, women with MS wouldn’t have to choose between what might be best for them and what is best for their baby,” she concluded.

SEATTLE—Women with multiple sclerosis (MS) may be able to reduce their risk for postpartum relapses by breastfeeding, according to findings that were presented at the 61st Annual Meeting of the American Academy of Neurology.

Previous studies have shown that breastfeeding may offer only limited protection against postpartum relapses in women with MS; however, these studies did not account for early supplemental infant formula feedings. Therefore, researchers from Stanford University and Northern California Kaiser Permanente Health Care System were interested in determining the effect of exclusive breastfeeding on risk of postpartum MS relapses, compared with not breastfeeding or breastfeeding combined with supplemental infant formula feedings.

“We prospectively followed 32 pregnant women with MS and 29 age-matched, pregnant controls and conducted structured interviews to assess clinical, menstrual, and breastfeeding history during each trimester and two, four, six, nine, and 12 months postpartum,” said Annette Langer-Gould, MD, a research scientist and neurologist at Kaiser Permanente Southern California. Patients were enrolled between 2002 and 2005.

Exclusive breastfeeding was defined as at least one bottle of breast milk per day, without regular supplemental infant formula feedings, for at least two months postpartum. “We chose the two-month cutoff, because we wanted it to be something that women could realistically achieve,” said Dr. Langer-Gould.

Exclusive Breastfeeding Appears to Be Protective
The researchers found that “fewer women with MS breastfed at all, compared to their healthy matched controls.” Fifty-two percent of women with MS did not breastfeed exclusively or began regular supplemental infant formula feedings within two months postpartum; of these, 87% had a postpartum relapse. In comparison, 36% of women who breastfed exclusively for at least two months postpartum had a relapse—in most cases, much later than women who did not breastfeed exclusively.

Seventy-three percent of women who decided to forego breastfeeding stated that they did so to resume MS therapies. Dr. Langer-Gould noted that more women who did not exclusively breastfeed had used immunomodulatory therapies in the year prior to becoming pregnant and might have had more frequent relapses prior to becoming pregnant as well, compared with women who breastfed exclusively. However, the effect of exclusive breastfeeding was still highly protective even after taking these factors into account.

Women who resumed MS therapies and did not breastfeed exclusively within the first two months postpartum had a significantly higher risk of postpartum relapses than women with MS who did not restart medications, regardless of breastfeeding status, noted Dr. Langer-Gould. These findings are interesting, she said, particularly because “our data certainly show that there is a belief that pregnant women with more severe disease should resume medications instead of breastfeeding after giving birth.”

Dr. Langer-Gould hypothesized that anovulation may play a role in protecting against postpartum relapse. Experimental autoimmune encephalitis models have shown that all states of anovulation appear to be protective against relapse, potentially explaining why pregnant women and women who exclusively breastfeed might show protection against relapse, she said. She noted that women who breastfed exclusively in the current study had a later return of menses.

Weighing the Risks and Benefits of Resuming Medications
“Our findings call into question the benefit of choosing not to breastfeed or stopping breastfeeding early to start taking MS therapies,” stated Dr. Langer-Gould. “Our study found no evidence that breastfeeding is harmful or that resuming MS medications is helpful in preventing postpartum relapses. Larger studies need to be done to establish whether breastfeeding exclusively is actually better than resuming medications.

“Future studies should also establish the safety of these medications during lactation, as has been done for antidepressants, which is a different concern than safety during pregnancy. That way, women with MS wouldn’t have to choose between what might be best for them and what is best for their baby,” she concluded.

SEATTLE—Women with multiple sclerosis (MS) may be able to reduce their risk for postpartum relapses by breastfeeding, according to findings that were presented at the 61st Annual Meeting of the American Academy of Neurology.

Previous studies have shown that breastfeeding may offer only limited protection against postpartum relapses in women with MS; however, these studies did not account for early supplemental infant formula feedings. Therefore, researchers from Stanford University and Northern California Kaiser Permanente Health Care System were interested in determining the effect of exclusive breastfeeding on risk of postpartum MS relapses, compared with not breastfeeding or breastfeeding combined with supplemental infant formula feedings.

“We prospectively followed 32 pregnant women with MS and 29 age-matched, pregnant controls and conducted structured interviews to assess clinical, menstrual, and breastfeeding history during each trimester and two, four, six, nine, and 12 months postpartum,” said Annette Langer-Gould, MD, a research scientist and neurologist at Kaiser Permanente Southern California. Patients were enrolled between 2002 and 2005.

Exclusive breastfeeding was defined as at least one bottle of breast milk per day, without regular supplemental infant formula feedings, for at least two months postpartum. “We chose the two-month cutoff, because we wanted it to be something that women could realistically achieve,” said Dr. Langer-Gould.

Exclusive Breastfeeding Appears to Be Protective
The researchers found that “fewer women with MS breastfed at all, compared to their healthy matched controls.” Fifty-two percent of women with MS did not breastfeed exclusively or began regular supplemental infant formula feedings within two months postpartum; of these, 87% had a postpartum relapse. In comparison, 36% of women who breastfed exclusively for at least two months postpartum had a relapse—in most cases, much later than women who did not breastfeed exclusively.

Seventy-three percent of women who decided to forego breastfeeding stated that they did so to resume MS therapies. Dr. Langer-Gould noted that more women who did not exclusively breastfeed had used immunomodulatory therapies in the year prior to becoming pregnant and might have had more frequent relapses prior to becoming pregnant as well, compared with women who breastfed exclusively. However, the effect of exclusive breastfeeding was still highly protective even after taking these factors into account.

Women who resumed MS therapies and did not breastfeed exclusively within the first two months postpartum had a significantly higher risk of postpartum relapses than women with MS who did not restart medications, regardless of breastfeeding status, noted Dr. Langer-Gould. These findings are interesting, she said, particularly because “our data certainly show that there is a belief that pregnant women with more severe disease should resume medications instead of breastfeeding after giving birth.”

Dr. Langer-Gould hypothesized that anovulation may play a role in protecting against postpartum relapse. Experimental autoimmune encephalitis models have shown that all states of anovulation appear to be protective against relapse, potentially explaining why pregnant women and women who exclusively breastfeed might show protection against relapse, she said. She noted that women who breastfed exclusively in the current study had a later return of menses.

Weighing the Risks and Benefits of Resuming Medications
“Our findings call into question the benefit of choosing not to breastfeed or stopping breastfeeding early to start taking MS therapies,” stated Dr. Langer-Gould. “Our study found no evidence that breastfeeding is harmful or that resuming MS medications is helpful in preventing postpartum relapses. Larger studies need to be done to establish whether breastfeeding exclusively is actually better than resuming medications.

“Future studies should also establish the safety of these medications during lactation, as has been done for antidepressants, which is a different concern than safety during pregnancy. That way, women with MS wouldn’t have to choose between what might be best for them and what is best for their baby,” she concluded.

SEATTLE—Patients with multiple sclerosis (MS) who take mitoxantrone have a significantly higher risk of leukemia than previously reported, according to research presented at the 61st Annual Meeting of the American Academy of Neurology. Vittorio Martinelli, MD, and colleagues found that acute leukemia occurred in 0.74% of patients with MS who took mitoxantrone, compared with prior studies that have reported leukemia rates ranging between 0.07% and 0.25% among those who had taken the drug.

Dr. Martinelli’s group included 2,854 Italian patients with MS who had been taking mitoxantrone since 1999 and observed them for at least one year. About 51% of patients had secondary progressive MS, 41% had relapsing-remitting MS, and 8% had primary progressive MS. Retrospective data were collected regarding total number of patients treated at each of the 35 MS centers in the study, cumulative dose of drug taken, and length of follow-up, noted Dr. Martinelli, who is a Head of the Department of Neurology and the Multiple Sclerosis Center at San Raffaele Institute in Milan.

Dr. Martinelli reported that 21 patients have developed acute leukemia thus far, and eight of these patients have died. The cumulative incidence of acute leukemia was 7.4 per 1,000, and the incidence rate was 0.16 per 1,000 person-months. Patients with acute leukemia had received a greater number of mitoxantrone administrations than did patients who did not have acute leukemia (8.6 treatment cycles vs 7.2, respectively), as well as a greater cumulative dose (82.4 vs 62.9 mg/m2, respectively).

Patients developed leukemia an average of 37 months after beginning mitoxantrone therapy and a mean of 18 months after the end of treatment. Using a cumulative dose of 82.4 mg/m2  or higher as an expositive factor, the researchers observed an incidence rate ratio of 2.74.

“The incidence of acute leukemia in Italian patients with MS treated with mitoxantrone is significantly higher than previously reported,” stated Dr. Martinelli. “The potential risk of acute leukemia should be carefully considered against the potential benefits of mitoxantrone treatment on every single patient.

“It is vital that all patients with MS treated with mitoxantrone undergo prolonged and careful hematologic follow-up to check for acute leukemia,” he concluded.

SEATTLE—Patients with multiple sclerosis (MS) who take mitoxantrone have a significantly higher risk of leukemia than previously reported, according to research presented at the 61st Annual Meeting of the American Academy of Neurology. Vittorio Martinelli, MD, and colleagues found that acute leukemia occurred in 0.74% of patients with MS who took mitoxantrone, compared with prior studies that have reported leukemia rates ranging between 0.07% and 0.25% among those who had taken the drug.

Dr. Martinelli’s group included 2,854 Italian patients with MS who had been taking mitoxantrone since 1999 and observed them for at least one year. About 51% of patients had secondary progressive MS, 41% had relapsing-remitting MS, and 8% had primary progressive MS. Retrospective data were collected regarding total number of patients treated at each of the 35 MS centers in the study, cumulative dose of drug taken, and length of follow-up, noted Dr. Martinelli, who is a Head of the Department of Neurology and the Multiple Sclerosis Center at San Raffaele Institute in Milan.

Dr. Martinelli reported that 21 patients have developed acute leukemia thus far, and eight of these patients have died. The cumulative incidence of acute leukemia was 7.4 per 1,000, and the incidence rate was 0.16 per 1,000 person-months. Patients with acute leukemia had received a greater number of mitoxantrone administrations than did patients who did not have acute leukemia (8.6 treatment cycles vs 7.2, respectively), as well as a greater cumulative dose (82.4 vs 62.9 mg/m2, respectively).

Patients developed leukemia an average of 37 months after beginning mitoxantrone therapy and a mean of 18 months after the end of treatment. Using a cumulative dose of 82.4 mg/m2  or higher as an expositive factor, the researchers observed an incidence rate ratio of 2.74.

“The incidence of acute leukemia in Italian patients with MS treated with mitoxantrone is significantly higher than previously reported,” stated Dr. Martinelli. “The potential risk of acute leukemia should be carefully considered against the potential benefits of mitoxantrone treatment on every single patient.

“It is vital that all patients with MS treated with mitoxantrone undergo prolonged and careful hematologic follow-up to check for acute leukemia,” he concluded.

SEATTLE—Patients with multiple sclerosis (MS) who take mitoxantrone have a significantly higher risk of leukemia than previously reported, according to research presented at the 61st Annual Meeting of the American Academy of Neurology. Vittorio Martinelli, MD, and colleagues found that acute leukemia occurred in 0.74% of patients with MS who took mitoxantrone, compared with prior studies that have reported leukemia rates ranging between 0.07% and 0.25% among those who had taken the drug.

Dr. Martinelli’s group included 2,854 Italian patients with MS who had been taking mitoxantrone since 1999 and observed them for at least one year. About 51% of patients had secondary progressive MS, 41% had relapsing-remitting MS, and 8% had primary progressive MS. Retrospective data were collected regarding total number of patients treated at each of the 35 MS centers in the study, cumulative dose of drug taken, and length of follow-up, noted Dr. Martinelli, who is a Head of the Department of Neurology and the Multiple Sclerosis Center at San Raffaele Institute in Milan.

Dr. Martinelli reported that 21 patients have developed acute leukemia thus far, and eight of these patients have died. The cumulative incidence of acute leukemia was 7.4 per 1,000, and the incidence rate was 0.16 per 1,000 person-months. Patients with acute leukemia had received a greater number of mitoxantrone administrations than did patients who did not have acute leukemia (8.6 treatment cycles vs 7.2, respectively), as well as a greater cumulative dose (82.4 vs 62.9 mg/m2, respectively).

Patients developed leukemia an average of 37 months after beginning mitoxantrone therapy and a mean of 18 months after the end of treatment. Using a cumulative dose of 82.4 mg/m2  or higher as an expositive factor, the researchers observed an incidence rate ratio of 2.74.

“The incidence of acute leukemia in Italian patients with MS treated with mitoxantrone is significantly higher than previously reported,” stated Dr. Martinelli. “The potential risk of acute leukemia should be carefully considered against the potential benefits of mitoxantrone treatment on every single patient.

“It is vital that all patients with MS treated with mitoxantrone undergo prolonged and careful hematologic follow-up to check for acute leukemia,” he concluded.

Patients with multiple sclerosis (MS) have a decreased overall cancer risk but have a higher risk of brain tumors and urinary organ cancer, according to a study published in the March 31 issue of Neurology. The lack of cancer risk among patients with MS likely does not result from an inherited characteristic, but rather from a behavioral change, treatment, or immunologic characteristic that improves antitumor surveillance, researchers reported.

Shahram Bahmanyar, MD, PhD, of the Clinical Epidemiology Unit in the Department of Medicine at Karolinska Institute in Karolinska Hospital in Stockholm, and colleagues estimated the disease risk among 20,276 patients with MS and 203,951 controls using data from the Swedish general population register. Similar analyses were completed among 11,284 fathers and 12,006 mothers of patients with MS, and also 123,158 fathers and 129,409 mothers of controls. The average length of follow-up was 35 years.

Overall, there was a decreased risk of cancer among patients with MS (hazard ratio [HR], 0.91). The risk for women was especially low. Follow-up beginning at the time of MS diagnosis showed little change (HR, 0.88). The risk was lower when, to ensure diagnostic accuracy, the analysis was restricted to MS register subjects and the relevant comparisons population (HR, 0.63). However, increased risks were observed for brain tumors (HR, 1.44) and urinary organ cancer (HR, 1.27). The average age of brain tumor diagnosis among patients with MS was 51.4, compared with 53.2 in the comparison group. An overall lower risk was observed among those who were diagnosed at earlier ages. Those diagnosed at age 20, between 20 and 34, and older than 34 had HRs of 0.32, 0.64, and 0.92, respectively. This effect was more pronounced among women, and an interaction test of age by gender produced a statistically significant HR of 0.974.

The overall cancer risk among parents of those with MS was not notably increased or decreased. Analysis of specific cancer sites did not show a protective or risk pattern. A modest increase for cancers of bone, kidney, and lymphoma among fathers was observed, along with an increase of endocrine cancers among mothers. “The lack of association among parents indicates that a simple inherited characteristic is unlikely to explain the reduced cancer risk among patients with MS,” Dr. Bahmanyar and colleagues stated.

“The lower cancer risk among patients with MS could be associated with lifestyle changes, treatment, disease-related activity, or a combination of these factors,” Dr. Bahmanyar and the study group suggested. Patients with MS often have a lower body mass index, which is a risk factor for some types of cancer. The researchers also speculated that cancer protection may result in part from the increase in systemic autoimmune responses against myelin antigens observed among patients.

“If autoimmune cells such as these react specifically against tumor autoantigens, this could represent an effective tumor defense mechanism,” the authors reported.

Patients with multiple sclerosis (MS) have a decreased overall cancer risk but have a higher risk of brain tumors and urinary organ cancer, according to a study published in the March 31 issue of Neurology. The lack of cancer risk among patients with MS likely does not result from an inherited characteristic, but rather from a behavioral change, treatment, or immunologic characteristic that improves antitumor surveillance, researchers reported.

Shahram Bahmanyar, MD, PhD, of the Clinical Epidemiology Unit in the Department of Medicine at Karolinska Institute in Karolinska Hospital in Stockholm, and colleagues estimated the disease risk among 20,276 patients with MS and 203,951 controls using data from the Swedish general population register. Similar analyses were completed among 11,284 fathers and 12,006 mothers of patients with MS, and also 123,158 fathers and 129,409 mothers of controls. The average length of follow-up was 35 years.

Overall, there was a decreased risk of cancer among patients with MS (hazard ratio [HR], 0.91). The risk for women was especially low. Follow-up beginning at the time of MS diagnosis showed little change (HR, 0.88). The risk was lower when, to ensure diagnostic accuracy, the analysis was restricted to MS register subjects and the relevant comparisons population (HR, 0.63). However, increased risks were observed for brain tumors (HR, 1.44) and urinary organ cancer (HR, 1.27). The average age of brain tumor diagnosis among patients with MS was 51.4, compared with 53.2 in the comparison group. An overall lower risk was observed among those who were diagnosed at earlier ages. Those diagnosed at age 20, between 20 and 34, and older than 34 had HRs of 0.32, 0.64, and 0.92, respectively. This effect was more pronounced among women, and an interaction test of age by gender produced a statistically significant HR of 0.974.

The overall cancer risk among parents of those with MS was not notably increased or decreased. Analysis of specific cancer sites did not show a protective or risk pattern. A modest increase for cancers of bone, kidney, and lymphoma among fathers was observed, along with an increase of endocrine cancers among mothers. “The lack of association among parents indicates that a simple inherited characteristic is unlikely to explain the reduced cancer risk among patients with MS,” Dr. Bahmanyar and colleagues stated.

“The lower cancer risk among patients with MS could be associated with lifestyle changes, treatment, disease-related activity, or a combination of these factors,” Dr. Bahmanyar and the study group suggested. Patients with MS often have a lower body mass index, which is a risk factor for some types of cancer. The researchers also speculated that cancer protection may result in part from the increase in systemic autoimmune responses against myelin antigens observed among patients.

“If autoimmune cells such as these react specifically against tumor autoantigens, this could represent an effective tumor defense mechanism,” the authors reported.

Patients with multiple sclerosis (MS) have a decreased overall cancer risk but have a higher risk of brain tumors and urinary organ cancer, according to a study published in the March 31 issue of Neurology. The lack of cancer risk among patients with MS likely does not result from an inherited characteristic, but rather from a behavioral change, treatment, or immunologic characteristic that improves antitumor surveillance, researchers reported.

Shahram Bahmanyar, MD, PhD, of the Clinical Epidemiology Unit in the Department of Medicine at Karolinska Institute in Karolinska Hospital in Stockholm, and colleagues estimated the disease risk among 20,276 patients with MS and 203,951 controls using data from the Swedish general population register. Similar analyses were completed among 11,284 fathers and 12,006 mothers of patients with MS, and also 123,158 fathers and 129,409 mothers of controls. The average length of follow-up was 35 years.

Overall, there was a decreased risk of cancer among patients with MS (hazard ratio [HR], 0.91). The risk for women was especially low. Follow-up beginning at the time of MS diagnosis showed little change (HR, 0.88). The risk was lower when, to ensure diagnostic accuracy, the analysis was restricted to MS register subjects and the relevant comparisons population (HR, 0.63). However, increased risks were observed for brain tumors (HR, 1.44) and urinary organ cancer (HR, 1.27). The average age of brain tumor diagnosis among patients with MS was 51.4, compared with 53.2 in the comparison group. An overall lower risk was observed among those who were diagnosed at earlier ages. Those diagnosed at age 20, between 20 and 34, and older than 34 had HRs of 0.32, 0.64, and 0.92, respectively. This effect was more pronounced among women, and an interaction test of age by gender produced a statistically significant HR of 0.974.

The overall cancer risk among parents of those with MS was not notably increased or decreased. Analysis of specific cancer sites did not show a protective or risk pattern. A modest increase for cancers of bone, kidney, and lymphoma among fathers was observed, along with an increase of endocrine cancers among mothers. “The lack of association among parents indicates that a simple inherited characteristic is unlikely to explain the reduced cancer risk among patients with MS,” Dr. Bahmanyar and colleagues stated.

“The lower cancer risk among patients with MS could be associated with lifestyle changes, treatment, disease-related activity, or a combination of these factors,” Dr. Bahmanyar and the study group suggested. Patients with MS often have a lower body mass index, which is a risk factor for some types of cancer. The researchers also speculated that cancer protection may result in part from the increase in systemic autoimmune responses against myelin antigens observed among patients.

“If autoimmune cells such as these react specifically against tumor autoantigens, this could represent an effective tumor defense mechanism,” the authors reported.

Urgent Treatment of Minor Strokes Improves Outcomes
NEW YORK, February 4 (Reuters Health)—Urgent evaluation and treatment of patients with minor strokes and transient ischemic attacks (TIAs) in a specialist outpatient clinic can reduce future hospital bed-days, costs, and disability at six months, new research shows.

In the initial analysis of the Early use of eXisting PREventive Strategies for Stroke (EXPRESS) study, urgent assessment and treatment cut the 90-day risk of repeat stroke by roughly 80%. In the current analysis, Dr. Peter M. Rothwell, from John Radcliffe Hospital, Oxford, UK, and colleagues looked at the impact on hospital admission, costs, and disability.

EXPRESS involved a comparison of stroke outcomes between April 2002 and September 2004, before the set-up of specialist outpatient clinics designed to expedite stroke treatment and assessment, and afterwards during the period October 2004 to March 2007. Unlike the standard clinics, these clinics did not require an appointment, and primary care doctors were advised to send all patients with suspected stroke or TIA to them immediately.

As reported in the March issue of the Lancet Neurology, the urgent stroke clinics were associated with significant reductions in the 90-day risk of fatal or disabling stroke and hospital admissions for recurrent stroke. Reductions in the overall and vascular-related number of hospital bed days also occurred, from 1957 to 672 bed days after the clinics began. For each patient referred to an urgent stroke clinic, a cost savings of £624 ($887) was realized, the report indicated.

Further studies are needed to assess the long-term benefits of urgent assessment and treatment of strokes in specialist clinics, the authors concluded.

In a related editorial, Dr. Naeem Dean and Dr. Ashfaq Shuaib, from Royal Alexandra Hospital and the University of Alberta, Edmonton, Canada, commented that “the care of patients with stroke and the prevention of further events in patients who present with TIA, will, unfortunately, always be suboptimum as long as we fail to equate TIA and stroke care in line with the way we manage patients with acute coronary disorders.”

They added, “We hope that the research work emanating from several stroke centers ... will bring awareness to this underrecognized and poorly treated but common condition.”

Lancet Neurol. 2009;8(3):218-219, 235-243.

Both Cortical and Subcortical Atrophy Involved in Amnesia of MS
NEW YORK, February 6 (Reuters Health)—Memory impairment in multiple sclerosis (MS) correlates with both mesial temporal (MTL) and deep grey matter (DGM) atrophy, researchers from the State University of New York at Buffalo have observed.

“We have compared the relative clinical significance of MTL and DGM atrophy and found evidence supporting significant and distinct contributions of each region to MS-associated memory disorder,” Dr. Ralph H. B. Benedict and colleagues reported in the February issue of the Journal of Neurology, Neurosurgery, and Psychiatry.

In the study, 50 patients with MS underwent structural brain MRI and neuropsychologic testing. The results suggest that DGM atrophy is the primary predictor of impairment in new learning and acquisition, whereas MTL atrophy plays a more critical role in the retention of recently learned information, as measured by 20- to 25-minute delayed recall and recognition tasks.

“This paper makes an important conceptual point—that the dementia of MS includes clinical features that are related to frontal-subcortical circuitry and MTL cortex pathology,” Dr. Benedict noted in comments to Reuters Health. “Understanding that MS patients can present with either or both helps doctors correctly describe and explain the cognitive presentation of MS patients, and in turn, provide better management of this aspect of the illness,” he added.

The current findings, the investigators said, “support a rationale for therapies directed at both the encoding and consolidation aspects of memory in MS.”

J Neurol Neurosurg Psychiatry. 2009;80(2):201-206.

Urgent Treatment of Minor Strokes Improves Outcomes
NEW YORK, February 4 (Reuters Health)—Urgent evaluation and treatment of patients with minor strokes and transient ischemic attacks (TIAs) in a specialist outpatient clinic can reduce future hospital bed-days, costs, and disability at six months, new research shows.

In the initial analysis of the Early use of eXisting PREventive Strategies for Stroke (EXPRESS) study, urgent assessment and treatment cut the 90-day risk of repeat stroke by roughly 80%. In the current analysis, Dr. Peter M. Rothwell, from John Radcliffe Hospital, Oxford, UK, and colleagues looked at the impact on hospital admission, costs, and disability.

EXPRESS involved a comparison of stroke outcomes between April 2002 and September 2004, before the set-up of specialist outpatient clinics designed to expedite stroke treatment and assessment, and afterwards during the period October 2004 to March 2007. Unlike the standard clinics, these clinics did not require an appointment, and primary care doctors were advised to send all patients with suspected stroke or TIA to them immediately.

As reported in the March issue of the Lancet Neurology, the urgent stroke clinics were associated with significant reductions in the 90-day risk of fatal or disabling stroke and hospital admissions for recurrent stroke. Reductions in the overall and vascular-related number of hospital bed days also occurred, from 1957 to 672 bed days after the clinics began. For each patient referred to an urgent stroke clinic, a cost savings of £624 ($887) was realized, the report indicated.

Further studies are needed to assess the long-term benefits of urgent assessment and treatment of strokes in specialist clinics, the authors concluded.

In a related editorial, Dr. Naeem Dean and Dr. Ashfaq Shuaib, from Royal Alexandra Hospital and the University of Alberta, Edmonton, Canada, commented that “the care of patients with stroke and the prevention of further events in patients who present with TIA, will, unfortunately, always be suboptimum as long as we fail to equate TIA and stroke care in line with the way we manage patients with acute coronary disorders.”

They added, “We hope that the research work emanating from several stroke centers ... will bring awareness to this underrecognized and poorly treated but common condition.”

Lancet Neurol. 2009;8(3):218-219, 235-243.

Both Cortical and Subcortical Atrophy Involved in Amnesia of MS
NEW YORK, February 6 (Reuters Health)—Memory impairment in multiple sclerosis (MS) correlates with both mesial temporal (MTL) and deep grey matter (DGM) atrophy, researchers from the State University of New York at Buffalo have observed.

“We have compared the relative clinical significance of MTL and DGM atrophy and found evidence supporting significant and distinct contributions of each region to MS-associated memory disorder,” Dr. Ralph H. B. Benedict and colleagues reported in the February issue of the Journal of Neurology, Neurosurgery, and Psychiatry.

In the study, 50 patients with MS underwent structural brain MRI and neuropsychologic testing. The results suggest that DGM atrophy is the primary predictor of impairment in new learning and acquisition, whereas MTL atrophy plays a more critical role in the retention of recently learned information, as measured by 20- to 25-minute delayed recall and recognition tasks.

“This paper makes an important conceptual point—that the dementia of MS includes clinical features that are related to frontal-subcortical circuitry and MTL cortex pathology,” Dr. Benedict noted in comments to Reuters Health. “Understanding that MS patients can present with either or both helps doctors correctly describe and explain the cognitive presentation of MS patients, and in turn, provide better management of this aspect of the illness,” he added.

The current findings, the investigators said, “support a rationale for therapies directed at both the encoding and consolidation aspects of memory in MS.”

J Neurol Neurosurg Psychiatry. 2009;80(2):201-206.

Urgent Treatment of Minor Strokes Improves Outcomes
NEW YORK, February 4 (Reuters Health)—Urgent evaluation and treatment of patients with minor strokes and transient ischemic attacks (TIAs) in a specialist outpatient clinic can reduce future hospital bed-days, costs, and disability at six months, new research shows.

In the initial analysis of the Early use of eXisting PREventive Strategies for Stroke (EXPRESS) study, urgent assessment and treatment cut the 90-day risk of repeat stroke by roughly 80%. In the current analysis, Dr. Peter M. Rothwell, from John Radcliffe Hospital, Oxford, UK, and colleagues looked at the impact on hospital admission, costs, and disability.

EXPRESS involved a comparison of stroke outcomes between April 2002 and September 2004, before the set-up of specialist outpatient clinics designed to expedite stroke treatment and assessment, and afterwards during the period October 2004 to March 2007. Unlike the standard clinics, these clinics did not require an appointment, and primary care doctors were advised to send all patients with suspected stroke or TIA to them immediately.

As reported in the March issue of the Lancet Neurology, the urgent stroke clinics were associated with significant reductions in the 90-day risk of fatal or disabling stroke and hospital admissions for recurrent stroke. Reductions in the overall and vascular-related number of hospital bed days also occurred, from 1957 to 672 bed days after the clinics began. For each patient referred to an urgent stroke clinic, a cost savings of £624 ($887) was realized, the report indicated.

Further studies are needed to assess the long-term benefits of urgent assessment and treatment of strokes in specialist clinics, the authors concluded.

In a related editorial, Dr. Naeem Dean and Dr. Ashfaq Shuaib, from Royal Alexandra Hospital and the University of Alberta, Edmonton, Canada, commented that “the care of patients with stroke and the prevention of further events in patients who present with TIA, will, unfortunately, always be suboptimum as long as we fail to equate TIA and stroke care in line with the way we manage patients with acute coronary disorders.”

They added, “We hope that the research work emanating from several stroke centers ... will bring awareness to this underrecognized and poorly treated but common condition.”

Lancet Neurol. 2009;8(3):218-219, 235-243.

Both Cortical and Subcortical Atrophy Involved in Amnesia of MS
NEW YORK, February 6 (Reuters Health)—Memory impairment in multiple sclerosis (MS) correlates with both mesial temporal (MTL) and deep grey matter (DGM) atrophy, researchers from the State University of New York at Buffalo have observed.

“We have compared the relative clinical significance of MTL and DGM atrophy and found evidence supporting significant and distinct contributions of each region to MS-associated memory disorder,” Dr. Ralph H. B. Benedict and colleagues reported in the February issue of the Journal of Neurology, Neurosurgery, and Psychiatry.

In the study, 50 patients with MS underwent structural brain MRI and neuropsychologic testing. The results suggest that DGM atrophy is the primary predictor of impairment in new learning and acquisition, whereas MTL atrophy plays a more critical role in the retention of recently learned information, as measured by 20- to 25-minute delayed recall and recognition tasks.

“This paper makes an important conceptual point—that the dementia of MS includes clinical features that are related to frontal-subcortical circuitry and MTL cortex pathology,” Dr. Benedict noted in comments to Reuters Health. “Understanding that MS patients can present with either or both helps doctors correctly describe and explain the cognitive presentation of MS patients, and in turn, provide better management of this aspect of the illness,” he added.

The current findings, the investigators said, “support a rationale for therapies directed at both the encoding and consolidation aspects of memory in MS.”

J Neurol Neurosurg Psychiatry. 2009;80(2):201-206.

SALT LAKE CITY—ST8SIA1 is a susceptibility gene for multiple sclerosis (MS) and is transmitted primarily paternally, according to research presented at the 133rd Annual Meeting of the American Neurological Association. The finding may lead to new approaches for understanding the molecular pathophysiology of MS, reported Seema Husain, PhD, Research Associate at the Institute of Genomic Medicine, University of Medicine and Dentistry of New Jersey in Newark, and colleagues.

Two independent studies involving single-nucleotide polymorphism (SNP) analysis and gene sequence were conducted. The allelic association of MS with polymorphisms in the ST8SIA1 gene, located on chromosome 12p12, was first found in a single three-generation Pennsylvania Dutch family, in which the rs4762896 SNP was segregated along with the HLA DR15/DQ6 haplotype in patients with MS. Similar observations were made in a study of 274 Australian family trios that had an affected child and unaffected parents. Within this sample, researchers reported evidence of transmission disequilibrium of the paternal alleles for three more SNPs—rs704219, rs2041906, and rs1558793.

In the Pennsylvania Dutch family, six members were diagnosed with clinically definite MS and one had clinically probable MS. The investigators found only rs4762896 segregate along with the HLA DR15/DQ6 haplotype in the seven affected individuals.

An examination of the Australian sample of 209 trios showed significantly increased transmission of paternal alleles for rs704219, rs2041906, and rs1558793. An additional 65 trios from Tasmania were also genotyped for these three SNPs, and the same trend was observed.

In an analysis of interaction between the SNPs typed in the extended Australian cohorts (rs704219, rs2041906, and rs1558793) and HLA DR15/DQ6, the trios were divided into DR15-positive (n = 145) and DR15-negative (n = 128) groups. Transmission disequilibrium test analysis was completed separately. Results were similar but less significant than those in the previous analysis. In addition, the Australian cohort partially shared one haplotype with the Pennsylvania Dutch family—the T allele of rs1558793 and the A allele of rs2041906.

“Our results suggest that ST8SIA1 may be an MS susceptibility gene possibly regulated by genomic imprinting,” said Dr. Husain and colleagues. “Outside of the immunoregulatory system, this is the first gene extensively involved in neuronal function and membrane structure to be implicated with MS.”

SALT LAKE CITY—ST8SIA1 is a susceptibility gene for multiple sclerosis (MS) and is transmitted primarily paternally, according to research presented at the 133rd Annual Meeting of the American Neurological Association. The finding may lead to new approaches for understanding the molecular pathophysiology of MS, reported Seema Husain, PhD, Research Associate at the Institute of Genomic Medicine, University of Medicine and Dentistry of New Jersey in Newark, and colleagues.

Two independent studies involving single-nucleotide polymorphism (SNP) analysis and gene sequence were conducted. The allelic association of MS with polymorphisms in the ST8SIA1 gene, located on chromosome 12p12, was first found in a single three-generation Pennsylvania Dutch family, in which the rs4762896 SNP was segregated along with the HLA DR15/DQ6 haplotype in patients with MS. Similar observations were made in a study of 274 Australian family trios that had an affected child and unaffected parents. Within this sample, researchers reported evidence of transmission disequilibrium of the paternal alleles for three more SNPs—rs704219, rs2041906, and rs1558793.

In the Pennsylvania Dutch family, six members were diagnosed with clinically definite MS and one had clinically probable MS. The investigators found only rs4762896 segregate along with the HLA DR15/DQ6 haplotype in the seven affected individuals.

An examination of the Australian sample of 209 trios showed significantly increased transmission of paternal alleles for rs704219, rs2041906, and rs1558793. An additional 65 trios from Tasmania were also genotyped for these three SNPs, and the same trend was observed.

In an analysis of interaction between the SNPs typed in the extended Australian cohorts (rs704219, rs2041906, and rs1558793) and HLA DR15/DQ6, the trios were divided into DR15-positive (n = 145) and DR15-negative (n = 128) groups. Transmission disequilibrium test analysis was completed separately. Results were similar but less significant than those in the previous analysis. In addition, the Australian cohort partially shared one haplotype with the Pennsylvania Dutch family—the T allele of rs1558793 and the A allele of rs2041906.

“Our results suggest that ST8SIA1 may be an MS susceptibility gene possibly regulated by genomic imprinting,” said Dr. Husain and colleagues. “Outside of the immunoregulatory system, this is the first gene extensively involved in neuronal function and membrane structure to be implicated with MS.”

SALT LAKE CITY—ST8SIA1 is a susceptibility gene for multiple sclerosis (MS) and is transmitted primarily paternally, according to research presented at the 133rd Annual Meeting of the American Neurological Association. The finding may lead to new approaches for understanding the molecular pathophysiology of MS, reported Seema Husain, PhD, Research Associate at the Institute of Genomic Medicine, University of Medicine and Dentistry of New Jersey in Newark, and colleagues.

Two independent studies involving single-nucleotide polymorphism (SNP) analysis and gene sequence were conducted. The allelic association of MS with polymorphisms in the ST8SIA1 gene, located on chromosome 12p12, was first found in a single three-generation Pennsylvania Dutch family, in which the rs4762896 SNP was segregated along with the HLA DR15/DQ6 haplotype in patients with MS. Similar observations were made in a study of 274 Australian family trios that had an affected child and unaffected parents. Within this sample, researchers reported evidence of transmission disequilibrium of the paternal alleles for three more SNPs—rs704219, rs2041906, and rs1558793.

In the Pennsylvania Dutch family, six members were diagnosed with clinically definite MS and one had clinically probable MS. The investigators found only rs4762896 segregate along with the HLA DR15/DQ6 haplotype in the seven affected individuals.

An examination of the Australian sample of 209 trios showed significantly increased transmission of paternal alleles for rs704219, rs2041906, and rs1558793. An additional 65 trios from Tasmania were also genotyped for these three SNPs, and the same trend was observed.

In an analysis of interaction between the SNPs typed in the extended Australian cohorts (rs704219, rs2041906, and rs1558793) and HLA DR15/DQ6, the trios were divided into DR15-positive (n = 145) and DR15-negative (n = 128) groups. Transmission disequilibrium test analysis was completed separately. Results were similar but less significant than those in the previous analysis. In addition, the Australian cohort partially shared one haplotype with the Pennsylvania Dutch family—the T allele of rs1558793 and the A allele of rs2041906.

“Our results suggest that ST8SIA1 may be an MS susceptibility gene possibly regulated by genomic imprinting,” said Dr. Husain and colleagues. “Outside of the immunoregulatory system, this is the first gene extensively involved in neuronal function and membrane structure to be implicated with MS.”

SALT LAKE CITY—Patients with multiple sclerosis (MS) who use glatiramer acetate have significantly fewer relapses and lower medical costs, compared with those who use interferon beta-1b, reported researchers at the 133rd Annual Meeting of the American Neurological Association.

A Retrospective Analysis
Kenneth P. Johnson, MD, Professor Emeritus of Neurology at the University of Maryland and Director of the Maryland Center for Multiple Sclerosis in Baltimore, and Maureen J. Lage, PhD, Managing Member of HealthMetrics Outcomes Research in Groton, Connecticut, retrospectively studied data from the i3 LabRx Database. This health claims database includes laboratory test results, hospitalization data, pharmacy data, and demographic information for more than 20 million individuals from a major US managed care organization. Data were collected from July 2001 through June 2006.

Patients were included in the continuous use cohort (n = 418) if they used either interferon beta-1b or glatiramer acetate continuously for at least 24 months.

Costs were calculated as direct medical costs, which included inpatient, outpatient, and prescription drug services. These were based on paid amounts (eg, insurer and health plan payments, copayments, and deductibles). All costs were converted to 2006 values using the medical component of the Consumer Price Index.

Relapse was defined as either a hospitalization with a primary diagnosis of MS or an outpatient visit with a diagnosis of MS accompanied by a prescription for steroids within seven days after the outpatient visit.

One hundred ten patients received interferon beta-1b (mean age, 43.96; 76% female) and 308 patients received glatiramer acetate (mean age, 44.23; 82% female). The mean number of outpatient prescription medications totaled 4.18 and 4.42, respectively. Approximately 98% of patients in both groups had commercial insurance.

Hypertension was the most frequent comorbidity, occurring in 19 patients in the interferon beta-1b group and 39 patients in the glatiramer acetate group. Other comorbidities included anxiety, depression, diabetes, and high cholesterol. Concomitant medication uses included adrenal, anticholinergic, anticonvulsant, antiviral, cerebral stimulant, genitourinary, and skeletal muscle agents.

Eleven patients from the interferon beta-1b group and 23 from the glatiramer acetate group had a preperiod hospitalization with MS diagnosis (ie, six months before the date of first use of interferon beta-1b or glatiramer acetate).

Interferon Beta-1b: Costlier, With More MS Relapses
According to Drs. Johnson and Lage, in the two years following initiation of therapy, subjects who received interferon beta-1b had a 10.92% chance of relapse, while those taking glatiramer acetate had a 2.09% risk. The two-year total direct medical costs associated with the use of interferon beta-1b was $53,185; this amount was greatly reduced for subjects taking glatiramer acetate, with a direct two-year cost of $48,130.

This study was limited by the use of an administrative claims database that included only patients with medical and prescription benefit coverage. The medical claims data precluded the use of physician- or patient-reported functioning. In addition, the study used a different method for defining relapses than those used in traditional clinical studies; however, the algorithm was applied equally to both groups. The authors also stated that the study focused only on direct medical costs, despite other research that has indicated that the indirect costs of MS are also large.

Results Depict “Real Life” Data
Despite these limitations, the results are consistent with prior research. “Based on all of the currently available published data, glatiramer acetate is not only better tolerated but also shows significantly better clinical efficacy than interferon beta-1b for relapsing MS and is less costly,” Dr. Johnson commented in an interview with Neurology Reviews.

“While this is a direct comparison of the two drugs, it differs from the recent head-to-head trial data. This analysis was of the outcomes over two years of MS patients [in the US] who were not rigidly defined, as is required in a clinical trial, but depended on personal treatment decisions of US physicians, mainly neurologists practicing in all regions of the US,” concluded Dr. Johnson. “In my view, this analysis comes closer to the ‘real life’ situation in the US.

SALT LAKE CITY—Patients with multiple sclerosis (MS) who use glatiramer acetate have significantly fewer relapses and lower medical costs, compared with those who use interferon beta-1b, reported researchers at the 133rd Annual Meeting of the American Neurological Association.

A Retrospective Analysis
Kenneth P. Johnson, MD, Professor Emeritus of Neurology at the University of Maryland and Director of the Maryland Center for Multiple Sclerosis in Baltimore, and Maureen J. Lage, PhD, Managing Member of HealthMetrics Outcomes Research in Groton, Connecticut, retrospectively studied data from the i3 LabRx Database. This health claims database includes laboratory test results, hospitalization data, pharmacy data, and demographic information for more than 20 million individuals from a major US managed care organization. Data were collected from July 2001 through June 2006.

Patients were included in the continuous use cohort (n = 418) if they used either interferon beta-1b or glatiramer acetate continuously for at least 24 months.

Costs were calculated as direct medical costs, which included inpatient, outpatient, and prescription drug services. These were based on paid amounts (eg, insurer and health plan payments, copayments, and deductibles). All costs were converted to 2006 values using the medical component of the Consumer Price Index.

Relapse was defined as either a hospitalization with a primary diagnosis of MS or an outpatient visit with a diagnosis of MS accompanied by a prescription for steroids within seven days after the outpatient visit.

One hundred ten patients received interferon beta-1b (mean age, 43.96; 76% female) and 308 patients received glatiramer acetate (mean age, 44.23; 82% female). The mean number of outpatient prescription medications totaled 4.18 and 4.42, respectively. Approximately 98% of patients in both groups had commercial insurance.

Hypertension was the most frequent comorbidity, occurring in 19 patients in the interferon beta-1b group and 39 patients in the glatiramer acetate group. Other comorbidities included anxiety, depression, diabetes, and high cholesterol. Concomitant medication uses included adrenal, anticholinergic, anticonvulsant, antiviral, cerebral stimulant, genitourinary, and skeletal muscle agents.

Eleven patients from the interferon beta-1b group and 23 from the glatiramer acetate group had a preperiod hospitalization with MS diagnosis (ie, six months before the date of first use of interferon beta-1b or glatiramer acetate).

Interferon Beta-1b: Costlier, With More MS Relapses
According to Drs. Johnson and Lage, in the two years following initiation of therapy, subjects who received interferon beta-1b had a 10.92% chance of relapse, while those taking glatiramer acetate had a 2.09% risk. The two-year total direct medical costs associated with the use of interferon beta-1b was $53,185; this amount was greatly reduced for subjects taking glatiramer acetate, with a direct two-year cost of $48,130.

This study was limited by the use of an administrative claims database that included only patients with medical and prescription benefit coverage. The medical claims data precluded the use of physician- or patient-reported functioning. In addition, the study used a different method for defining relapses than those used in traditional clinical studies; however, the algorithm was applied equally to both groups. The authors also stated that the study focused only on direct medical costs, despite other research that has indicated that the indirect costs of MS are also large.

Results Depict “Real Life” Data
Despite these limitations, the results are consistent with prior research. “Based on all of the currently available published data, glatiramer acetate is not only better tolerated but also shows significantly better clinical efficacy than interferon beta-1b for relapsing MS and is less costly,” Dr. Johnson commented in an interview with Neurology Reviews.

“While this is a direct comparison of the two drugs, it differs from the recent head-to-head trial data. This analysis was of the outcomes over two years of MS patients [in the US] who were not rigidly defined, as is required in a clinical trial, but depended on personal treatment decisions of US physicians, mainly neurologists practicing in all regions of the US,” concluded Dr. Johnson. “In my view, this analysis comes closer to the ‘real life’ situation in the US.

SALT LAKE CITY—Patients with multiple sclerosis (MS) who use glatiramer acetate have significantly fewer relapses and lower medical costs, compared with those who use interferon beta-1b, reported researchers at the 133rd Annual Meeting of the American Neurological Association.

A Retrospective Analysis
Kenneth P. Johnson, MD, Professor Emeritus of Neurology at the University of Maryland and Director of the Maryland Center for Multiple Sclerosis in Baltimore, and Maureen J. Lage, PhD, Managing Member of HealthMetrics Outcomes Research in Groton, Connecticut, retrospectively studied data from the i3 LabRx Database. This health claims database includes laboratory test results, hospitalization data, pharmacy data, and demographic information for more than 20 million individuals from a major US managed care organization. Data were collected from July 2001 through June 2006.

Patients were included in the continuous use cohort (n = 418) if they used either interferon beta-1b or glatiramer acetate continuously for at least 24 months.

Costs were calculated as direct medical costs, which included inpatient, outpatient, and prescription drug services. These were based on paid amounts (eg, insurer and health plan payments, copayments, and deductibles). All costs were converted to 2006 values using the medical component of the Consumer Price Index.

Relapse was defined as either a hospitalization with a primary diagnosis of MS or an outpatient visit with a diagnosis of MS accompanied by a prescription for steroids within seven days after the outpatient visit.

One hundred ten patients received interferon beta-1b (mean age, 43.96; 76% female) and 308 patients received glatiramer acetate (mean age, 44.23; 82% female). The mean number of outpatient prescription medications totaled 4.18 and 4.42, respectively. Approximately 98% of patients in both groups had commercial insurance.

Hypertension was the most frequent comorbidity, occurring in 19 patients in the interferon beta-1b group and 39 patients in the glatiramer acetate group. Other comorbidities included anxiety, depression, diabetes, and high cholesterol. Concomitant medication uses included adrenal, anticholinergic, anticonvulsant, antiviral, cerebral stimulant, genitourinary, and skeletal muscle agents.

Eleven patients from the interferon beta-1b group and 23 from the glatiramer acetate group had a preperiod hospitalization with MS diagnosis (ie, six months before the date of first use of interferon beta-1b or glatiramer acetate).

Interferon Beta-1b: Costlier, With More MS Relapses
According to Drs. Johnson and Lage, in the two years following initiation of therapy, subjects who received interferon beta-1b had a 10.92% chance of relapse, while those taking glatiramer acetate had a 2.09% risk. The two-year total direct medical costs associated with the use of interferon beta-1b was $53,185; this amount was greatly reduced for subjects taking glatiramer acetate, with a direct two-year cost of $48,130.

This study was limited by the use of an administrative claims database that included only patients with medical and prescription benefit coverage. The medical claims data precluded the use of physician- or patient-reported functioning. In addition, the study used a different method for defining relapses than those used in traditional clinical studies; however, the algorithm was applied equally to both groups. The authors also stated that the study focused only on direct medical costs, despite other research that has indicated that the indirect costs of MS are also large.

Results Depict “Real Life” Data
Despite these limitations, the results are consistent with prior research. “Based on all of the currently available published data, glatiramer acetate is not only better tolerated but also shows significantly better clinical efficacy than interferon beta-1b for relapsing MS and is less costly,” Dr. Johnson commented in an interview with Neurology Reviews.

“While this is a direct comparison of the two drugs, it differs from the recent head-to-head trial data. This analysis was of the outcomes over two years of MS patients [in the US] who were not rigidly defined, as is required in a clinical trial, but depended on personal treatment decisions of US physicians, mainly neurologists practicing in all regions of the US,” concluded Dr. Johnson. “In my view, this analysis comes closer to the ‘real life’ situation in the US.

MONTREAL—Treating patients with multiple sclerosis (MS) who have breakthrough disease activity despite the use of disease-modifying drug therapy requires identification of suboptimal responders, a monitoring strategy, and consideration of largely unproven treatment approaches, said Richard A. Rudick, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis.

“A large proportion of patients with relapsing-remitting MS will show signs of disease activity within one to two years,” said Dr. Rudick. “This is not necessarily a poor response to therapy; this is expected.”

In published phase III trials, 62% to 75% of patients with relapsing-remitting MS had one or more relapses within two years while on disease-modifying drug therapy, about one fourth had a sustained increase in Expanded Disability Status Scale score, about one fourth had one or more gadolinium (Gd)-enhancing lesions, and more than half had one or more new T2 lesions.

Identifying nonresponders, therefore, is the first consideration in managing true breakthrough disease, said Dr. Rudick, Director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic. Patient self-report and the physician’s global impression of change are usually the initial approaches, although the validity of these approaches has not been studied.

Relapses do not appear to be a reliable marker for response to a disease-modifying drug, according to Dr. Rudick. In placebo-controlled clinical studies, many patients who remain on placebo will have fewer relapses in year 2 than in year 1—a regression to the mean phenomenon. Reliance on relapse data—especially from studies in which patients are crossed over from placebo to treatment after a length of time—to justify a switch of therapy is therefore misleading, said Dr. Rudick, who is also Vice Chairman of Research and Development in the Neurological Institute at Cleveland Clinic and Professor of Medicine in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

“MRI findings are considerably more promising,” he said. Several studies suggest that Gd-enhancing lesions or T2 lesions developing while on treatment are reliable indicators of suboptimal response or nonresponse to interferon treatment.

Dr. Rudick cited a study in which 383 patients with clinically isolated syndrome underwent MRI scans every six months for up to 18 months. Among patients treated with interferon beta-1a, those who developed at least one Gd-enhancing lesion, or two or more T2 lesions, at six months had nearly four times the risk of converting to clinically definite MS within 30 months (hazard ratio, 3.94), compared with treated patients who had no Gd-enhancing lesions and/or less than two T2 lesions at six months.

MRI activity “appears to be a marker at six months that identifies progression over the subsequent 18 months and is predominantly seen in the treated groups, so this appears to be a treatment response marker,” said Dr. Rudick. “We may not need to wait for one or two years.” The same predictor has not been studied in groups treated with glatiramer acetate, he noted.

At this point, there is no reliable biomarker for response or nonresponse to interferon or glatiramer acetate. However, “multiple studies by groups worldwide have documented a blunted or absent biologic and clinical response to interferon in patients with high titer neutralizing antibodies,” he said.

Managing patients with breakthrough disease starts with a monitoring strategy, asserted Dr. Rudick. “I see patients semiannually for a history and physical. I do an annual MRI scan, and I always consider the possibility of noncompliance. Patients don’t volunteer that they’re not taking their medication,” he said.

Next, he recommends deciding how much disease activity is tolerable. “I believe this has to be individualized,” he said. “In many patients, an occasional relapse is not only anticipated, but it may be okay. You need to consider how well the individual patient recovers from relapses.”

More aggressive management would be warranted in those patients who recover poorly from relapses. “For patients on interferon, I check neutralizing antibodies if I’m in doubt, and some argue that all patients on interferon should have antibodies tested,” he said.

For patients with unacceptable levels of disease activity, clinicians should consider changing therapy “probably earlier rather than later,” Dr. Rudick advised. Switching between interferon products and glatiramer acetate is a common practice for patients with breakthrough disease, but there are no randomized controlled trials to support this practice. Regression to the mean will drive the appearance of switching toward benefit. Dr. Rudick recommended that treatment should only be switched when a patient develops neutralizing antibodies while on interferon, in which case the patient should be switched to glatiramer acetate.

Combination therapy for suboptimal responders is also common but not supported by strong evidence. Combination therapy has had “disappointing” results in randomized clinical trials, he said, and may increase the incidence of side effects, compared with monotherapy.

Dr. Rudick noted that his treatment of choice in patients with disease activity while on disease-modifying drug therapy is natalizumab. Symptomatic therapy and rehabilitation should not be forgotten for patients during the process of monitoring and managing patients with disease-modifying drugs.

“I think we need realistic expectations,” he said. “There are no drugs labeled for progressive MS, because there is no established efficacy in this category of patient.” He added that caution should be exercised when considering off-label use of drugs that are in phase II studies.

Dr. Rudick concluded that randomized controlled trials of alternative monotherapies or combination therapies are needed for patients with breakthrough disease, as are methods to stratify patients for treatment selection and biomarkers to predict individual response to therapy.

MONTREAL—Treating patients with multiple sclerosis (MS) who have breakthrough disease activity despite the use of disease-modifying drug therapy requires identification of suboptimal responders, a monitoring strategy, and consideration of largely unproven treatment approaches, said Richard A. Rudick, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis.

“A large proportion of patients with relapsing-remitting MS will show signs of disease activity within one to two years,” said Dr. Rudick. “This is not necessarily a poor response to therapy; this is expected.”

In published phase III trials, 62% to 75% of patients with relapsing-remitting MS had one or more relapses within two years while on disease-modifying drug therapy, about one fourth had a sustained increase in Expanded Disability Status Scale score, about one fourth had one or more gadolinium (Gd)-enhancing lesions, and more than half had one or more new T2 lesions.

Identifying nonresponders, therefore, is the first consideration in managing true breakthrough disease, said Dr. Rudick, Director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic. Patient self-report and the physician’s global impression of change are usually the initial approaches, although the validity of these approaches has not been studied.

Relapses do not appear to be a reliable marker for response to a disease-modifying drug, according to Dr. Rudick. In placebo-controlled clinical studies, many patients who remain on placebo will have fewer relapses in year 2 than in year 1—a regression to the mean phenomenon. Reliance on relapse data—especially from studies in which patients are crossed over from placebo to treatment after a length of time—to justify a switch of therapy is therefore misleading, said Dr. Rudick, who is also Vice Chairman of Research and Development in the Neurological Institute at Cleveland Clinic and Professor of Medicine in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

“MRI findings are considerably more promising,” he said. Several studies suggest that Gd-enhancing lesions or T2 lesions developing while on treatment are reliable indicators of suboptimal response or nonresponse to interferon treatment.

Dr. Rudick cited a study in which 383 patients with clinically isolated syndrome underwent MRI scans every six months for up to 18 months. Among patients treated with interferon beta-1a, those who developed at least one Gd-enhancing lesion, or two or more T2 lesions, at six months had nearly four times the risk of converting to clinically definite MS within 30 months (hazard ratio, 3.94), compared with treated patients who had no Gd-enhancing lesions and/or less than two T2 lesions at six months.

MRI activity “appears to be a marker at six months that identifies progression over the subsequent 18 months and is predominantly seen in the treated groups, so this appears to be a treatment response marker,” said Dr. Rudick. “We may not need to wait for one or two years.” The same predictor has not been studied in groups treated with glatiramer acetate, he noted.

At this point, there is no reliable biomarker for response or nonresponse to interferon or glatiramer acetate. However, “multiple studies by groups worldwide have documented a blunted or absent biologic and clinical response to interferon in patients with high titer neutralizing antibodies,” he said.

Managing patients with breakthrough disease starts with a monitoring strategy, asserted Dr. Rudick. “I see patients semiannually for a history and physical. I do an annual MRI scan, and I always consider the possibility of noncompliance. Patients don’t volunteer that they’re not taking their medication,” he said.

Next, he recommends deciding how much disease activity is tolerable. “I believe this has to be individualized,” he said. “In many patients, an occasional relapse is not only anticipated, but it may be okay. You need to consider how well the individual patient recovers from relapses.”

More aggressive management would be warranted in those patients who recover poorly from relapses. “For patients on interferon, I check neutralizing antibodies if I’m in doubt, and some argue that all patients on interferon should have antibodies tested,” he said.

For patients with unacceptable levels of disease activity, clinicians should consider changing therapy “probably earlier rather than later,” Dr. Rudick advised. Switching between interferon products and glatiramer acetate is a common practice for patients with breakthrough disease, but there are no randomized controlled trials to support this practice. Regression to the mean will drive the appearance of switching toward benefit. Dr. Rudick recommended that treatment should only be switched when a patient develops neutralizing antibodies while on interferon, in which case the patient should be switched to glatiramer acetate.

Combination therapy for suboptimal responders is also common but not supported by strong evidence. Combination therapy has had “disappointing” results in randomized clinical trials, he said, and may increase the incidence of side effects, compared with monotherapy.

Dr. Rudick noted that his treatment of choice in patients with disease activity while on disease-modifying drug therapy is natalizumab. Symptomatic therapy and rehabilitation should not be forgotten for patients during the process of monitoring and managing patients with disease-modifying drugs.

“I think we need realistic expectations,” he said. “There are no drugs labeled for progressive MS, because there is no established efficacy in this category of patient.” He added that caution should be exercised when considering off-label use of drugs that are in phase II studies.

Dr. Rudick concluded that randomized controlled trials of alternative monotherapies or combination therapies are needed for patients with breakthrough disease, as are methods to stratify patients for treatment selection and biomarkers to predict individual response to therapy.

MONTREAL—Treating patients with multiple sclerosis (MS) who have breakthrough disease activity despite the use of disease-modifying drug therapy requires identification of suboptimal responders, a monitoring strategy, and consideration of largely unproven treatment approaches, said Richard A. Rudick, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis.

“A large proportion of patients with relapsing-remitting MS will show signs of disease activity within one to two years,” said Dr. Rudick. “This is not necessarily a poor response to therapy; this is expected.”

In published phase III trials, 62% to 75% of patients with relapsing-remitting MS had one or more relapses within two years while on disease-modifying drug therapy, about one fourth had a sustained increase in Expanded Disability Status Scale score, about one fourth had one or more gadolinium (Gd)-enhancing lesions, and more than half had one or more new T2 lesions.

Identifying nonresponders, therefore, is the first consideration in managing true breakthrough disease, said Dr. Rudick, Director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic. Patient self-report and the physician’s global impression of change are usually the initial approaches, although the validity of these approaches has not been studied.

Relapses do not appear to be a reliable marker for response to a disease-modifying drug, according to Dr. Rudick. In placebo-controlled clinical studies, many patients who remain on placebo will have fewer relapses in year 2 than in year 1—a regression to the mean phenomenon. Reliance on relapse data—especially from studies in which patients are crossed over from placebo to treatment after a length of time—to justify a switch of therapy is therefore misleading, said Dr. Rudick, who is also Vice Chairman of Research and Development in the Neurological Institute at Cleveland Clinic and Professor of Medicine in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

“MRI findings are considerably more promising,” he said. Several studies suggest that Gd-enhancing lesions or T2 lesions developing while on treatment are reliable indicators of suboptimal response or nonresponse to interferon treatment.

Dr. Rudick cited a study in which 383 patients with clinically isolated syndrome underwent MRI scans every six months for up to 18 months. Among patients treated with interferon beta-1a, those who developed at least one Gd-enhancing lesion, or two or more T2 lesions, at six months had nearly four times the risk of converting to clinically definite MS within 30 months (hazard ratio, 3.94), compared with treated patients who had no Gd-enhancing lesions and/or less than two T2 lesions at six months.

MRI activity “appears to be a marker at six months that identifies progression over the subsequent 18 months and is predominantly seen in the treated groups, so this appears to be a treatment response marker,” said Dr. Rudick. “We may not need to wait for one or two years.” The same predictor has not been studied in groups treated with glatiramer acetate, he noted.

At this point, there is no reliable biomarker for response or nonresponse to interferon or glatiramer acetate. However, “multiple studies by groups worldwide have documented a blunted or absent biologic and clinical response to interferon in patients with high titer neutralizing antibodies,” he said.

Managing patients with breakthrough disease starts with a monitoring strategy, asserted Dr. Rudick. “I see patients semiannually for a history and physical. I do an annual MRI scan, and I always consider the possibility of noncompliance. Patients don’t volunteer that they’re not taking their medication,” he said.

Next, he recommends deciding how much disease activity is tolerable. “I believe this has to be individualized,” he said. “In many patients, an occasional relapse is not only anticipated, but it may be okay. You need to consider how well the individual patient recovers from relapses.”

More aggressive management would be warranted in those patients who recover poorly from relapses. “For patients on interferon, I check neutralizing antibodies if I’m in doubt, and some argue that all patients on interferon should have antibodies tested,” he said.

For patients with unacceptable levels of disease activity, clinicians should consider changing therapy “probably earlier rather than later,” Dr. Rudick advised. Switching between interferon products and glatiramer acetate is a common practice for patients with breakthrough disease, but there are no randomized controlled trials to support this practice. Regression to the mean will drive the appearance of switching toward benefit. Dr. Rudick recommended that treatment should only be switched when a patient develops neutralizing antibodies while on interferon, in which case the patient should be switched to glatiramer acetate.

Combination therapy for suboptimal responders is also common but not supported by strong evidence. Combination therapy has had “disappointing” results in randomized clinical trials, he said, and may increase the incidence of side effects, compared with monotherapy.

Dr. Rudick noted that his treatment of choice in patients with disease activity while on disease-modifying drug therapy is natalizumab. Symptomatic therapy and rehabilitation should not be forgotten for patients during the process of monitoring and managing patients with disease-modifying drugs.

“I think we need realistic expectations,” he said. “There are no drugs labeled for progressive MS, because there is no established efficacy in this category of patient.” He added that caution should be exercised when considering off-label use of drugs that are in phase II studies.

Dr. Rudick concluded that randomized controlled trials of alternative monotherapies or combination therapies are needed for patients with breakthrough disease, as are methods to stratify patients for treatment selection and biomarkers to predict individual response to therapy.

MONTREAL—Pediatric-onset acute demyelination provides a unique window for studying environmental exposure and disease mechanisms involved in multiple sclerosis (MS), said Brenda Banwell, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis. Some of the triggers being studied in children include viral exposure (eg, Epstein-Barr virus [EBV]) and vitamin D deficiency.

“Pediatric acute demyelination provides an opportunity to look at a population of individuals presenting at a time when they have had a relatively limited environmental experience, when the immune attack may be directed at the primary target involved in the MS disease process with a reduced possibility of secondary immune responses to injured tissue,” said Dr. Banwell, Associate Professor of Pediatrics (Neurology) and Director of the Pediatric Multiple Sclerosis and Demyelinating Disease Program at the Hospital for Sick Children, University of Toronto. In pediatric MS, the targets become available to the immune system potentially at a time when the environmental exposures, or triggers of the disease, are still operative.

Dr. Banwell and colleagues obtained data from the Canadian National Pediatric Demyelinating Disease Study, a prospective study involving 23 sites across Canada. Children with a first demyelinating event were enrolled at presentation and underwent a comprehensive clinical, genetic, pathobiologic, and neuroimaging assessment, which was performed at three, six, and 12 months, and then annually thereafter.

EBV as a Possible Trigger
A viral pathogen of interest as a potential trigger of MS is EBV. “EBV has a very powerful effect on our immune system; when you acquire EBV infection, you never really lose it,” she said. “It becomes part of our B-cell repertoire, and it’s a part of our repertoire that we have to tightly control.”

She described a study of 137 children with MS and 96 controls matched by age and geographic region who underwent standardized assays for immunoglobulin G antibodies directed against EBV, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus.

“We found that when you compare children with MS to non-MS participants, the MS children do indeed have higher titer reactions to the EBV protein,” she said. A greater percentage of children with MS were in the high-titer group (area under the curve > 195), compared with age-matched, EBV-positive healthy controls (40% vs 18%).

Serial samples demonstrated that “high titers persist,” she said. “It’s not a transient phenomenon.”

Is Vitamin D Insufficiency Linked to MS?
More than 80% of the children with MS were seropositive for EBV infection, a significantly higher rate than that observed in controls. Children with MS did not differ from controls in seroprevalence of the other viruses studied.

The high rate of MS in Canada may be related to vitamin D insufficiency, said Dr. Banwell. Canada has one of the highest rates of MS in the world, and distance from the equator is one variable that has been shown to be associated with MS prevalence. One of the more popular theories is that suboptimal vitamin D synthesis in the skin may play a role in the pathobiology of MS.

Therefore, Dr. Banwell and colleagues evaluated vitamin D status in 117 children with a first attack of demyelination who were enrolled in the Canadian National Pediatric Demyelinating Disease Study; 98 had monophasic acquired demyelination syndrome (ADS) at the time of the study, and 19 were diagnosed with MS.

The mean serum level of 25-hydroxyvitamin D was 61.3 nmol/L at presentation in the children with monophasic ADS, which was significantly greater than the 44.2-nmol/L mean level at presentation in the children who were later diagnosed with MS. The mean level of serum 25-hydroxyvitamin D value for the entire group of 117 children was 58.5 nmol/L, “well below what is considered to be a reasonable vitamin D level in serum, which is 75 nmol/L,” said Dr. Banwell.

More than 75% of the entire cohort were vitamin D–insufficient. Of the children in the lowest quartile of serum 25-hydroxyvitamin D level (≤ 34.8 nmol/L), 28% were diagnosed with MS, compared with 7% of children with serum 25-hydroxyvitamin D levels in the highest quartile (> 76.3 nmol/L).

Assessing Immunologic Biomarkers
Several immunologic biomarkers and their association with pediatric MS have also been studied. Dr. Banwell’s research team conducted one such study of serum biomarkers in children with clinically isolated syndrome and age- and gender-matched healthy children. In this study, children with demyelination had higher levels of matrix metalloproteinase (a marker of potential immune cell entry into the CNS), reduced levels of tumor necrosis factor–related apoptosis-inducing ligand, which is a potential biomarker of reduced apoptosis of inflammatory cells, and reduced levels of interleukin 10 (indicating a reduction in anti-inflammatory activity), compared with healthy controls.

MONTREAL—Pediatric-onset acute demyelination provides a unique window for studying environmental exposure and disease mechanisms involved in multiple sclerosis (MS), said Brenda Banwell, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis. Some of the triggers being studied in children include viral exposure (eg, Epstein-Barr virus [EBV]) and vitamin D deficiency.

“Pediatric acute demyelination provides an opportunity to look at a population of individuals presenting at a time when they have had a relatively limited environmental experience, when the immune attack may be directed at the primary target involved in the MS disease process with a reduced possibility of secondary immune responses to injured tissue,” said Dr. Banwell, Associate Professor of Pediatrics (Neurology) and Director of the Pediatric Multiple Sclerosis and Demyelinating Disease Program at the Hospital for Sick Children, University of Toronto. In pediatric MS, the targets become available to the immune system potentially at a time when the environmental exposures, or triggers of the disease, are still operative.

Dr. Banwell and colleagues obtained data from the Canadian National Pediatric Demyelinating Disease Study, a prospective study involving 23 sites across Canada. Children with a first demyelinating event were enrolled at presentation and underwent a comprehensive clinical, genetic, pathobiologic, and neuroimaging assessment, which was performed at three, six, and 12 months, and then annually thereafter.

EBV as a Possible Trigger
A viral pathogen of interest as a potential trigger of MS is EBV. “EBV has a very powerful effect on our immune system; when you acquire EBV infection, you never really lose it,” she said. “It becomes part of our B-cell repertoire, and it’s a part of our repertoire that we have to tightly control.”

She described a study of 137 children with MS and 96 controls matched by age and geographic region who underwent standardized assays for immunoglobulin G antibodies directed against EBV, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus.

“We found that when you compare children with MS to non-MS participants, the MS children do indeed have higher titer reactions to the EBV protein,” she said. A greater percentage of children with MS were in the high-titer group (area under the curve > 195), compared with age-matched, EBV-positive healthy controls (40% vs 18%).

Serial samples demonstrated that “high titers persist,” she said. “It’s not a transient phenomenon.”

Is Vitamin D Insufficiency Linked to MS?
More than 80% of the children with MS were seropositive for EBV infection, a significantly higher rate than that observed in controls. Children with MS did not differ from controls in seroprevalence of the other viruses studied.

The high rate of MS in Canada may be related to vitamin D insufficiency, said Dr. Banwell. Canada has one of the highest rates of MS in the world, and distance from the equator is one variable that has been shown to be associated with MS prevalence. One of the more popular theories is that suboptimal vitamin D synthesis in the skin may play a role in the pathobiology of MS.

Therefore, Dr. Banwell and colleagues evaluated vitamin D status in 117 children with a first attack of demyelination who were enrolled in the Canadian National Pediatric Demyelinating Disease Study; 98 had monophasic acquired demyelination syndrome (ADS) at the time of the study, and 19 were diagnosed with MS.

The mean serum level of 25-hydroxyvitamin D was 61.3 nmol/L at presentation in the children with monophasic ADS, which was significantly greater than the 44.2-nmol/L mean level at presentation in the children who were later diagnosed with MS. The mean level of serum 25-hydroxyvitamin D value for the entire group of 117 children was 58.5 nmol/L, “well below what is considered to be a reasonable vitamin D level in serum, which is 75 nmol/L,” said Dr. Banwell.

More than 75% of the entire cohort were vitamin D–insufficient. Of the children in the lowest quartile of serum 25-hydroxyvitamin D level (≤ 34.8 nmol/L), 28% were diagnosed with MS, compared with 7% of children with serum 25-hydroxyvitamin D levels in the highest quartile (> 76.3 nmol/L).

Assessing Immunologic Biomarkers
Several immunologic biomarkers and their association with pediatric MS have also been studied. Dr. Banwell’s research team conducted one such study of serum biomarkers in children with clinically isolated syndrome and age- and gender-matched healthy children. In this study, children with demyelination had higher levels of matrix metalloproteinase (a marker of potential immune cell entry into the CNS), reduced levels of tumor necrosis factor–related apoptosis-inducing ligand, which is a potential biomarker of reduced apoptosis of inflammatory cells, and reduced levels of interleukin 10 (indicating a reduction in anti-inflammatory activity), compared with healthy controls.

MONTREAL—Pediatric-onset acute demyelination provides a unique window for studying environmental exposure and disease mechanisms involved in multiple sclerosis (MS), said Brenda Banwell, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis. Some of the triggers being studied in children include viral exposure (eg, Epstein-Barr virus [EBV]) and vitamin D deficiency.

“Pediatric acute demyelination provides an opportunity to look at a population of individuals presenting at a time when they have had a relatively limited environmental experience, when the immune attack may be directed at the primary target involved in the MS disease process with a reduced possibility of secondary immune responses to injured tissue,” said Dr. Banwell, Associate Professor of Pediatrics (Neurology) and Director of the Pediatric Multiple Sclerosis and Demyelinating Disease Program at the Hospital for Sick Children, University of Toronto. In pediatric MS, the targets become available to the immune system potentially at a time when the environmental exposures, or triggers of the disease, are still operative.

Dr. Banwell and colleagues obtained data from the Canadian National Pediatric Demyelinating Disease Study, a prospective study involving 23 sites across Canada. Children with a first demyelinating event were enrolled at presentation and underwent a comprehensive clinical, genetic, pathobiologic, and neuroimaging assessment, which was performed at three, six, and 12 months, and then annually thereafter.

EBV as a Possible Trigger
A viral pathogen of interest as a potential trigger of MS is EBV. “EBV has a very powerful effect on our immune system; when you acquire EBV infection, you never really lose it,” she said. “It becomes part of our B-cell repertoire, and it’s a part of our repertoire that we have to tightly control.”

She described a study of 137 children with MS and 96 controls matched by age and geographic region who underwent standardized assays for immunoglobulin G antibodies directed against EBV, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus.

“We found that when you compare children with MS to non-MS participants, the MS children do indeed have higher titer reactions to the EBV protein,” she said. A greater percentage of children with MS were in the high-titer group (area under the curve > 195), compared with age-matched, EBV-positive healthy controls (40% vs 18%).

Serial samples demonstrated that “high titers persist,” she said. “It’s not a transient phenomenon.”

Is Vitamin D Insufficiency Linked to MS?
More than 80% of the children with MS were seropositive for EBV infection, a significantly higher rate than that observed in controls. Children with MS did not differ from controls in seroprevalence of the other viruses studied.

The high rate of MS in Canada may be related to vitamin D insufficiency, said Dr. Banwell. Canada has one of the highest rates of MS in the world, and distance from the equator is one variable that has been shown to be associated with MS prevalence. One of the more popular theories is that suboptimal vitamin D synthesis in the skin may play a role in the pathobiology of MS.

Therefore, Dr. Banwell and colleagues evaluated vitamin D status in 117 children with a first attack of demyelination who were enrolled in the Canadian National Pediatric Demyelinating Disease Study; 98 had monophasic acquired demyelination syndrome (ADS) at the time of the study, and 19 were diagnosed with MS.

The mean serum level of 25-hydroxyvitamin D was 61.3 nmol/L at presentation in the children with monophasic ADS, which was significantly greater than the 44.2-nmol/L mean level at presentation in the children who were later diagnosed with MS. The mean level of serum 25-hydroxyvitamin D value for the entire group of 117 children was 58.5 nmol/L, “well below what is considered to be a reasonable vitamin D level in serum, which is 75 nmol/L,” said Dr. Banwell.

More than 75% of the entire cohort were vitamin D–insufficient. Of the children in the lowest quartile of serum 25-hydroxyvitamin D level (≤ 34.8 nmol/L), 28% were diagnosed with MS, compared with 7% of children with serum 25-hydroxyvitamin D levels in the highest quartile (> 76.3 nmol/L).

Assessing Immunologic Biomarkers
Several immunologic biomarkers and their association with pediatric MS have also been studied. Dr. Banwell’s research team conducted one such study of serum biomarkers in children with clinically isolated syndrome and age- and gender-matched healthy children. In this study, children with demyelination had higher levels of matrix metalloproteinase (a marker of potential immune cell entry into the CNS), reduced levels of tumor necrosis factor–related apoptosis-inducing ligand, which is a potential biomarker of reduced apoptosis of inflammatory cells, and reduced levels of interleukin 10 (indicating a reduction in anti-inflammatory activity), compared with healthy controls.