Multiple Sclerosis

Neuropsychiatric Systemic Lupus Erythematosus

Imaging can play an important role in ruling out other causes of neuropsychiatric systemic lupus erythematosus (NPSLE), which could be caused by SLE-mediated organ dysfunction, infection, medication side effects, metabolic abnormalities, or an unrelated condition, according to Dr. Patricia C. Cagnoli, a rheumatologist at the University of Michigan in Ann Arbor.

“You have to figure out if the [NPSLE] symptoms are related to the lupus,” Dr. Cagnoli said. But “we don't have any specific imaging technique that can tell you that.”

The diagnostic approach also depends in part on the presentation. Are the symptoms focal or acute or more diffuse? For example, in the case of acute symptoms, CT can help rule out ischemic strokes, large tumors, and massive bleeds—the most acute and urgent conditions that would require immediate treatment/surgery. If a patient has more diffuse symptoms, infection should be ruled out first with a lumbar puncture in addition to imaging.

“MRI is probably the cornerstone imaging technique to use in the diagnosis of neuropsychiatric lupus,” Dr. Cagnoli said. Multiple imaging sequences and intravenous administration of contrast are employed to accurately delineate abnormal areas in the brain. “More often than not, MRI will reveal several lesions that were not detected by CT scanning.” These areas of new injury are likely capable of responding to treatment and healing in ways that cannot be seen by CT.

MRI also frequently identifies small bright spots in the subcortical white matter that are of uncertain significance and are sometimes referred to as “unidentified bright objects,” or UBOs.

“Most of the patients with neuropsychiatric lupus will have these hyperintense white matter lesions, but so do apparently normal individuals,” she said.

These lesions are not specific to NPSLE. It's not uncommon for patients to have small white-matter lesions on MRI that are considered to be areas of possible demyelinization, similar to multiple sclerosis. In fact, patients are often referred to Dr. Cagnoli's group to help determine if patients have MS or lupus with CNS involvement. MS lesions tend to be bigger, to coalesce, and to progress quickly.

However, imaging is only part of the picture. “It's the rest of your physical assessment, your clinical impression, your laboratory evaluation that will tell you, in the end, what it is,” she said.

Functional MRI techniques such as MR spectroscopy, diffusion-weighted imaging, and diffusion tensor imaging (DTI) are beginning to reveal which patients have functional abnormalities.

When comparing structural and functional MRI, “you have a normal conventional MRI and you see already evidence of neuronal loss or brain injury in the functional MRI,” Dr. Cagnoli said.

The researchers hope to use these techniques to identify patients with preclinical NPSLE-type lesions, in order to begin treatment as early as possible. “Eventually, our hope is that we might be able to treat these patients sooner rather than later,” she said. “One of the problems we have with [NPSLE] is trying to identify those patients” who require earlier and more aggressive treatment, “as opposed to those patients who can benefit from a more conservative approach.”

NPSLE requires treatment not just for the neuropsychiatric symptoms, with antipsychotics for psychosis as an example, but also for the underlying SLE, with immunosuppressants and high doses of corticosteroids. “So you treat the symptom—psychosis is the symptom in this case—but also the underlying mechanism, which is the lupus,” said Dr. Cagnoli, who is also the associate director of the Michigan Lupus Program.

She and several colleagues are currently enrolling patients in a pilot study to evaluate whether MR spectroscopy, MR perfusion imaging, and MR DTI can detect alterations in brain function distinctive for NPSLE and compare the findings with those found in an existing cohort of 20 normal, healthy controls.

MRI shows NPSLE lesions with fluid attenuated inversion recovery (FLAIR), T2-weighted, and T1-weighted, gadolinium contrast sequences. Courtesy Dr. Pia Maly-Sundgren

Neuropsychiatric Systemic Lupus Erythematosus

Imaging can play an important role in ruling out other causes of neuropsychiatric systemic lupus erythematosus (NPSLE), which could be caused by SLE-mediated organ dysfunction, infection, medication side effects, metabolic abnormalities, or an unrelated condition, according to Dr. Patricia C. Cagnoli, a rheumatologist at the University of Michigan in Ann Arbor.

“You have to figure out if the [NPSLE] symptoms are related to the lupus,” Dr. Cagnoli said. But “we don't have any specific imaging technique that can tell you that.”

The diagnostic approach also depends in part on the presentation. Are the symptoms focal or acute or more diffuse? For example, in the case of acute symptoms, CT can help rule out ischemic strokes, large tumors, and massive bleeds—the most acute and urgent conditions that would require immediate treatment/surgery. If a patient has more diffuse symptoms, infection should be ruled out first with a lumbar puncture in addition to imaging.

“MRI is probably the cornerstone imaging technique to use in the diagnosis of neuropsychiatric lupus,” Dr. Cagnoli said. Multiple imaging sequences and intravenous administration of contrast are employed to accurately delineate abnormal areas in the brain. “More often than not, MRI will reveal several lesions that were not detected by CT scanning.” These areas of new injury are likely capable of responding to treatment and healing in ways that cannot be seen by CT.

MRI also frequently identifies small bright spots in the subcortical white matter that are of uncertain significance and are sometimes referred to as “unidentified bright objects,” or UBOs.

“Most of the patients with neuropsychiatric lupus will have these hyperintense white matter lesions, but so do apparently normal individuals,” she said.

These lesions are not specific to NPSLE. It's not uncommon for patients to have small white-matter lesions on MRI that are considered to be areas of possible demyelinization, similar to multiple sclerosis. In fact, patients are often referred to Dr. Cagnoli's group to help determine if patients have MS or lupus with CNS involvement. MS lesions tend to be bigger, to coalesce, and to progress quickly.

However, imaging is only part of the picture. “It's the rest of your physical assessment, your clinical impression, your laboratory evaluation that will tell you, in the end, what it is,” she said.

Functional MRI techniques such as MR spectroscopy, diffusion-weighted imaging, and diffusion tensor imaging (DTI) are beginning to reveal which patients have functional abnormalities.

When comparing structural and functional MRI, “you have a normal conventional MRI and you see already evidence of neuronal loss or brain injury in the functional MRI,” Dr. Cagnoli said.

The researchers hope to use these techniques to identify patients with preclinical NPSLE-type lesions, in order to begin treatment as early as possible. “Eventually, our hope is that we might be able to treat these patients sooner rather than later,” she said. “One of the problems we have with [NPSLE] is trying to identify those patients” who require earlier and more aggressive treatment, “as opposed to those patients who can benefit from a more conservative approach.”

NPSLE requires treatment not just for the neuropsychiatric symptoms, with antipsychotics for psychosis as an example, but also for the underlying SLE, with immunosuppressants and high doses of corticosteroids. “So you treat the symptom—psychosis is the symptom in this case—but also the underlying mechanism, which is the lupus,” said Dr. Cagnoli, who is also the associate director of the Michigan Lupus Program.

She and several colleagues are currently enrolling patients in a pilot study to evaluate whether MR spectroscopy, MR perfusion imaging, and MR DTI can detect alterations in brain function distinctive for NPSLE and compare the findings with those found in an existing cohort of 20 normal, healthy controls.

MRI shows NPSLE lesions with fluid attenuated inversion recovery (FLAIR), T2-weighted, and T1-weighted, gadolinium contrast sequences. Courtesy Dr. Pia Maly-Sundgren

Neuropsychiatric Systemic Lupus Erythematosus

Imaging can play an important role in ruling out other causes of neuropsychiatric systemic lupus erythematosus (NPSLE), which could be caused by SLE-mediated organ dysfunction, infection, medication side effects, metabolic abnormalities, or an unrelated condition, according to Dr. Patricia C. Cagnoli, a rheumatologist at the University of Michigan in Ann Arbor.

“You have to figure out if the [NPSLE] symptoms are related to the lupus,” Dr. Cagnoli said. But “we don't have any specific imaging technique that can tell you that.”

The diagnostic approach also depends in part on the presentation. Are the symptoms focal or acute or more diffuse? For example, in the case of acute symptoms, CT can help rule out ischemic strokes, large tumors, and massive bleeds—the most acute and urgent conditions that would require immediate treatment/surgery. If a patient has more diffuse symptoms, infection should be ruled out first with a lumbar puncture in addition to imaging.

“MRI is probably the cornerstone imaging technique to use in the diagnosis of neuropsychiatric lupus,” Dr. Cagnoli said. Multiple imaging sequences and intravenous administration of contrast are employed to accurately delineate abnormal areas in the brain. “More often than not, MRI will reveal several lesions that were not detected by CT scanning.” These areas of new injury are likely capable of responding to treatment and healing in ways that cannot be seen by CT.

MRI also frequently identifies small bright spots in the subcortical white matter that are of uncertain significance and are sometimes referred to as “unidentified bright objects,” or UBOs.

“Most of the patients with neuropsychiatric lupus will have these hyperintense white matter lesions, but so do apparently normal individuals,” she said.

These lesions are not specific to NPSLE. It's not uncommon for patients to have small white-matter lesions on MRI that are considered to be areas of possible demyelinization, similar to multiple sclerosis. In fact, patients are often referred to Dr. Cagnoli's group to help determine if patients have MS or lupus with CNS involvement. MS lesions tend to be bigger, to coalesce, and to progress quickly.

However, imaging is only part of the picture. “It's the rest of your physical assessment, your clinical impression, your laboratory evaluation that will tell you, in the end, what it is,” she said.

Functional MRI techniques such as MR spectroscopy, diffusion-weighted imaging, and diffusion tensor imaging (DTI) are beginning to reveal which patients have functional abnormalities.

When comparing structural and functional MRI, “you have a normal conventional MRI and you see already evidence of neuronal loss or brain injury in the functional MRI,” Dr. Cagnoli said.

The researchers hope to use these techniques to identify patients with preclinical NPSLE-type lesions, in order to begin treatment as early as possible. “Eventually, our hope is that we might be able to treat these patients sooner rather than later,” she said. “One of the problems we have with [NPSLE] is trying to identify those patients” who require earlier and more aggressive treatment, “as opposed to those patients who can benefit from a more conservative approach.”

NPSLE requires treatment not just for the neuropsychiatric symptoms, with antipsychotics for psychosis as an example, but also for the underlying SLE, with immunosuppressants and high doses of corticosteroids. “So you treat the symptom—psychosis is the symptom in this case—but also the underlying mechanism, which is the lupus,” said Dr. Cagnoli, who is also the associate director of the Michigan Lupus Program.

She and several colleagues are currently enrolling patients in a pilot study to evaluate whether MR spectroscopy, MR perfusion imaging, and MR DTI can detect alterations in brain function distinctive for NPSLE and compare the findings with those found in an existing cohort of 20 normal, healthy controls.

MRI shows NPSLE lesions with fluid attenuated inversion recovery (FLAIR), T2-weighted, and T1-weighted, gadolinium contrast sequences. Courtesy Dr. Pia Maly-Sundgren

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.

Vitamin D appears to interact directly with a key susceptibility locus for multiple sclerosis, serving as an environmental influence that may decrease the risk of the disease in individuals with certain haplotypes, according to a study reported online in PLoS Genetics.

The findings provide “more direct support for the already strong epidemiological evidence implicating sunlight and vitamin D in the determination of MS [multiple sclerosis] risk, and implies that vitamin D supplementation at critical time periods may be key to disease prevention,” Sreeram V. Ramagopalan, D.Phil., of the University of Oxford (England) and associates reported (PLoS Genetics 2009 Feb. 6 [doi:10.1371/journal.pgen.1000369]).

The prevalence of MS has been shown to decrease across a north-to-south gradient in the northern hemisphere and increase across a north-to-south gradient in the southern hemisphere. Other studies found that patients with MS are deficient in vitamin D, and dietary intake of the vitamin reduces MS risk. Data also suggest that MS risk in the northern latitudes of the northern hemisphere may vary with the season of birth.

However, the association between MS risk and the chromosomal region that the researchers focused on is “weak at best,” even though it is the region known to be most strongly associated with MS in Northern Europeans, Dr. Mark S. Freedman said in an interview.

“As you go around the world… there may well be other HLA susceptibility genes, but we just haven't been able to identify the exact ones,” said Dr. Freedman, director of the multiple sclerosis research unit at Ottawa (Ont.) Hospital and professor of neurology at the University of Ottawa. He was not involved in the study.

Dr. Freedman also noted that the association between vitamin D and MS does not explain why dark-skinned people can develop MS.

In a cell line that carried HLA-DRB1*15, Dr. Ramagopalan and colleagues discovered a functional vitamin D response element (VDRE) near the transcription start of the gene HLA-DRB1, which is located in the large genomic region containing major histocompatibility complex (MHC) class II genes.

The sequence of the VDRE was the same in 322 individuals with or without MS who were homozygous for the HLA-DRB1*15 risk allele. However, nucleotide changes in the VDRE sequences were detected in 168 individuals who were homozygous for other HLA-DRB1 alleles. In a cell line that carried the HLA-DRB1*15 haplotype, the putative VDRE was able to bind to vitamin D receptor, which is known to influence “the rate of transcription of vitamin D responsive genes by acting as a ligand activated transcription factor,” according to the investigators.

Dr. Ramagopalan and coinvestigators then showed that the addition of 1,25-dihydroxyvitmin D3, or calcitriol, to HLA-DRB1 gene constructs with this VDRE significantly increased expression of the HLA-DRB1 gene by 60%. Treatment with 1,25-dihydroxyvitamin D3 also significantly increased the expression of HLA-DRB1 by 30% on the surface of cells that were homozygous for the HLA-DRB1*15 haplotype.

“Given the results of this study, variable expression of HLA-DRB1 could affect central deletion of autoreactive T cells. It is plausible that a lack of vitamin D in utero or early childhood can affect the expression of HLA-DRB1 in the thymus, impacting on central deletion. For MS in HLA-DRB1*15 bearing individuals, a lack of vitamin D during early life could allow autoreactive T cells to escape thymic deletion and thus increase autoimmune disease risk.”

“The intriguing possibility that vitamin D responsiveness rather than any antigen specificity determines the increased MS risk of the HLA-DRB1*15 haplotype warrants consideration and can be tested in the infrequent haplotypes bearing the VDRE on other non-HLA-DRB1*15 haplotypes,” the researchers concluded.

The study was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom.

Vitamin D appears to interact directly with a key susceptibility locus for multiple sclerosis, serving as an environmental influence that may decrease the risk of the disease in individuals with certain haplotypes, according to a study reported online in PLoS Genetics.

The findings provide “more direct support for the already strong epidemiological evidence implicating sunlight and vitamin D in the determination of MS [multiple sclerosis] risk, and implies that vitamin D supplementation at critical time periods may be key to disease prevention,” Sreeram V. Ramagopalan, D.Phil., of the University of Oxford (England) and associates reported (PLoS Genetics 2009 Feb. 6 [doi:10.1371/journal.pgen.1000369]).

The prevalence of MS has been shown to decrease across a north-to-south gradient in the northern hemisphere and increase across a north-to-south gradient in the southern hemisphere. Other studies found that patients with MS are deficient in vitamin D, and dietary intake of the vitamin reduces MS risk. Data also suggest that MS risk in the northern latitudes of the northern hemisphere may vary with the season of birth.

However, the association between MS risk and the chromosomal region that the researchers focused on is “weak at best,” even though it is the region known to be most strongly associated with MS in Northern Europeans, Dr. Mark S. Freedman said in an interview.

“As you go around the world… there may well be other HLA susceptibility genes, but we just haven't been able to identify the exact ones,” said Dr. Freedman, director of the multiple sclerosis research unit at Ottawa (Ont.) Hospital and professor of neurology at the University of Ottawa. He was not involved in the study.

Dr. Freedman also noted that the association between vitamin D and MS does not explain why dark-skinned people can develop MS.

In a cell line that carried HLA-DRB1*15, Dr. Ramagopalan and colleagues discovered a functional vitamin D response element (VDRE) near the transcription start of the gene HLA-DRB1, which is located in the large genomic region containing major histocompatibility complex (MHC) class II genes.

The sequence of the VDRE was the same in 322 individuals with or without MS who were homozygous for the HLA-DRB1*15 risk allele. However, nucleotide changes in the VDRE sequences were detected in 168 individuals who were homozygous for other HLA-DRB1 alleles. In a cell line that carried the HLA-DRB1*15 haplotype, the putative VDRE was able to bind to vitamin D receptor, which is known to influence “the rate of transcription of vitamin D responsive genes by acting as a ligand activated transcription factor,” according to the investigators.

Dr. Ramagopalan and coinvestigators then showed that the addition of 1,25-dihydroxyvitmin D3, or calcitriol, to HLA-DRB1 gene constructs with this VDRE significantly increased expression of the HLA-DRB1 gene by 60%. Treatment with 1,25-dihydroxyvitamin D3 also significantly increased the expression of HLA-DRB1 by 30% on the surface of cells that were homozygous for the HLA-DRB1*15 haplotype.

“Given the results of this study, variable expression of HLA-DRB1 could affect central deletion of autoreactive T cells. It is plausible that a lack of vitamin D in utero or early childhood can affect the expression of HLA-DRB1 in the thymus, impacting on central deletion. For MS in HLA-DRB1*15 bearing individuals, a lack of vitamin D during early life could allow autoreactive T cells to escape thymic deletion and thus increase autoimmune disease risk.”

“The intriguing possibility that vitamin D responsiveness rather than any antigen specificity determines the increased MS risk of the HLA-DRB1*15 haplotype warrants consideration and can be tested in the infrequent haplotypes bearing the VDRE on other non-HLA-DRB1*15 haplotypes,” the researchers concluded.

The study was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom.

Vitamin D appears to interact directly with a key susceptibility locus for multiple sclerosis, serving as an environmental influence that may decrease the risk of the disease in individuals with certain haplotypes, according to a study reported online in PLoS Genetics.

The findings provide “more direct support for the already strong epidemiological evidence implicating sunlight and vitamin D in the determination of MS [multiple sclerosis] risk, and implies that vitamin D supplementation at critical time periods may be key to disease prevention,” Sreeram V. Ramagopalan, D.Phil., of the University of Oxford (England) and associates reported (PLoS Genetics 2009 Feb. 6 [doi:10.1371/journal.pgen.1000369]).

The prevalence of MS has been shown to decrease across a north-to-south gradient in the northern hemisphere and increase across a north-to-south gradient in the southern hemisphere. Other studies found that patients with MS are deficient in vitamin D, and dietary intake of the vitamin reduces MS risk. Data also suggest that MS risk in the northern latitudes of the northern hemisphere may vary with the season of birth.

However, the association between MS risk and the chromosomal region that the researchers focused on is “weak at best,” even though it is the region known to be most strongly associated with MS in Northern Europeans, Dr. Mark S. Freedman said in an interview.

“As you go around the world… there may well be other HLA susceptibility genes, but we just haven't been able to identify the exact ones,” said Dr. Freedman, director of the multiple sclerosis research unit at Ottawa (Ont.) Hospital and professor of neurology at the University of Ottawa. He was not involved in the study.

Dr. Freedman also noted that the association between vitamin D and MS does not explain why dark-skinned people can develop MS.

In a cell line that carried HLA-DRB1*15, Dr. Ramagopalan and colleagues discovered a functional vitamin D response element (VDRE) near the transcription start of the gene HLA-DRB1, which is located in the large genomic region containing major histocompatibility complex (MHC) class II genes.

The sequence of the VDRE was the same in 322 individuals with or without MS who were homozygous for the HLA-DRB1*15 risk allele. However, nucleotide changes in the VDRE sequences were detected in 168 individuals who were homozygous for other HLA-DRB1 alleles. In a cell line that carried the HLA-DRB1*15 haplotype, the putative VDRE was able to bind to vitamin D receptor, which is known to influence “the rate of transcription of vitamin D responsive genes by acting as a ligand activated transcription factor,” according to the investigators.

Dr. Ramagopalan and coinvestigators then showed that the addition of 1,25-dihydroxyvitmin D3, or calcitriol, to HLA-DRB1 gene constructs with this VDRE significantly increased expression of the HLA-DRB1 gene by 60%. Treatment with 1,25-dihydroxyvitamin D3 also significantly increased the expression of HLA-DRB1 by 30% on the surface of cells that were homozygous for the HLA-DRB1*15 haplotype.

“Given the results of this study, variable expression of HLA-DRB1 could affect central deletion of autoreactive T cells. It is plausible that a lack of vitamin D in utero or early childhood can affect the expression of HLA-DRB1 in the thymus, impacting on central deletion. For MS in HLA-DRB1*15 bearing individuals, a lack of vitamin D during early life could allow autoreactive T cells to escape thymic deletion and thus increase autoimmune disease risk.”

“The intriguing possibility that vitamin D responsiveness rather than any antigen specificity determines the increased MS risk of the HLA-DRB1*15 haplotype warrants consideration and can be tested in the infrequent haplotypes bearing the VDRE on other non-HLA-DRB1*15 haplotypes,” the researchers concluded.

The study was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom.

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.

MADRID — Glatiramer acetate significantly reduced relapse and disease progression in patients with multiple sclerosis who received the drug after a course of methotrexate, according to the results of a small Italian study.

“In our experience, six multiple sclerosis patients treated with methotrexate followed by glatiramer acetate showed a significant reduction of inflammatory activity parameters during the follow-up,” Dr. Yasmin Handouk wrote in a poster that was presented at the annual congress of the European Federation of Neurological Societies.

“This was associated with a lack of disease progression,” Dr. Handouk added.

Glatiramer acetate received Food and Drug Administration approval in 2001 for use in reduction of the frequency of relapses in relapsing-remitting multiple sclerosis.

The randomized trial included 12 patients with refractory MS (6 with relapsing-remitting disease and 6 with progressive-relapsing disease).

All of the patients had undergone a course of methotrexate after failing to respond to interferon therapy, wrote Dr. Handouk of the Università Politecnica delle Marche, Ancona, Italy.

After methotrexate, patients had magnetic resonance imaging of the brain. Within 3 months of ending methotrexate, six started maintenance therapy with glatiramer acetate 20 mg/day for a mean of 8 months; the rest received no further treatment.

Follow-up assessments were done at 6-month intervals for 2 years.

At the 2-year follow-up, only one patient in the active group had relapsed. Disability, as measured by the Expanded Disability Status Scale, had significantly improved, with patients dropping an average of 1 point on the scale.

There were no new or enhanced lesions.

In the nontreated group, two patients had relapsed. The disability score was not improved from baseline. Two patients showed new gadolinium-enhancing lesions.

“[Dr. Jason Ramtahal] previously proved the usefulness of 6-month glatiramer acetate beginning 2 months before ending methotrexate, although a case of acute promyelocytic leukemia was registered [J. Neuro. 2006;253:1160–4],” Dr. Handouk noted.

“Our patients started glatiramer acetate therapy at least 3 months after methotrexate without serious adverse event.”

Dr. Handouk made no financial declarations with regard to the study.

MADRID — Glatiramer acetate significantly reduced relapse and disease progression in patients with multiple sclerosis who received the drug after a course of methotrexate, according to the results of a small Italian study.

“In our experience, six multiple sclerosis patients treated with methotrexate followed by glatiramer acetate showed a significant reduction of inflammatory activity parameters during the follow-up,” Dr. Yasmin Handouk wrote in a poster that was presented at the annual congress of the European Federation of Neurological Societies.

“This was associated with a lack of disease progression,” Dr. Handouk added.

Glatiramer acetate received Food and Drug Administration approval in 2001 for use in reduction of the frequency of relapses in relapsing-remitting multiple sclerosis.

The randomized trial included 12 patients with refractory MS (6 with relapsing-remitting disease and 6 with progressive-relapsing disease).

All of the patients had undergone a course of methotrexate after failing to respond to interferon therapy, wrote Dr. Handouk of the Università Politecnica delle Marche, Ancona, Italy.

After methotrexate, patients had magnetic resonance imaging of the brain. Within 3 months of ending methotrexate, six started maintenance therapy with glatiramer acetate 20 mg/day for a mean of 8 months; the rest received no further treatment.

Follow-up assessments were done at 6-month intervals for 2 years.

At the 2-year follow-up, only one patient in the active group had relapsed. Disability, as measured by the Expanded Disability Status Scale, had significantly improved, with patients dropping an average of 1 point on the scale.

There were no new or enhanced lesions.

In the nontreated group, two patients had relapsed. The disability score was not improved from baseline. Two patients showed new gadolinium-enhancing lesions.

“[Dr. Jason Ramtahal] previously proved the usefulness of 6-month glatiramer acetate beginning 2 months before ending methotrexate, although a case of acute promyelocytic leukemia was registered [J. Neuro. 2006;253:1160–4],” Dr. Handouk noted.

“Our patients started glatiramer acetate therapy at least 3 months after methotrexate without serious adverse event.”

Dr. Handouk made no financial declarations with regard to the study.

MADRID — Glatiramer acetate significantly reduced relapse and disease progression in patients with multiple sclerosis who received the drug after a course of methotrexate, according to the results of a small Italian study.

“In our experience, six multiple sclerosis patients treated with methotrexate followed by glatiramer acetate showed a significant reduction of inflammatory activity parameters during the follow-up,” Dr. Yasmin Handouk wrote in a poster that was presented at the annual congress of the European Federation of Neurological Societies.

“This was associated with a lack of disease progression,” Dr. Handouk added.

Glatiramer acetate received Food and Drug Administration approval in 2001 for use in reduction of the frequency of relapses in relapsing-remitting multiple sclerosis.

The randomized trial included 12 patients with refractory MS (6 with relapsing-remitting disease and 6 with progressive-relapsing disease).

All of the patients had undergone a course of methotrexate after failing to respond to interferon therapy, wrote Dr. Handouk of the Università Politecnica delle Marche, Ancona, Italy.

After methotrexate, patients had magnetic resonance imaging of the brain. Within 3 months of ending methotrexate, six started maintenance therapy with glatiramer acetate 20 mg/day for a mean of 8 months; the rest received no further treatment.

Follow-up assessments were done at 6-month intervals for 2 years.

At the 2-year follow-up, only one patient in the active group had relapsed. Disability, as measured by the Expanded Disability Status Scale, had significantly improved, with patients dropping an average of 1 point on the scale.

There were no new or enhanced lesions.

In the nontreated group, two patients had relapsed. The disability score was not improved from baseline. Two patients showed new gadolinium-enhancing lesions.

“[Dr. Jason Ramtahal] previously proved the usefulness of 6-month glatiramer acetate beginning 2 months before ending methotrexate, although a case of acute promyelocytic leukemia was registered [J. Neuro. 2006;253:1160–4],” Dr. Handouk noted.

“Our patients started glatiramer acetate therapy at least 3 months after methotrexate without serious adverse event.”

Dr. Handouk made no financial declarations with regard to the study.