Multiple Sclerosis Hub

Stroke After Cardiac Surgery and Role of Carotid Stenosis
Combining carotid and cardiac procedures is neither necessary nor effective in reducing postoperative stroke in patients with asymptomatic carotid stenosis, according to a study in the September Archives of Neurology. Researchers found no direct causal relationship between significant carotid stenosis and postoperative stroke in patients who underwent cardiac operations.

Yuebing Li, MD, PhD, and colleagues at Lehigh Valley Hospital and Health Network in Allentown, Pennsylvania, reviewed data of 4,335 patients receiving nonurgent coronary artery bypass grafting (CABG) and/or aortic valve replacement between July 2001 and December 2006. Prior to surgery, 3,942 patients were evaluated for carotid stenosis using high-resolution sonography, 239 (6.1%) of whom were identified as having significant carotid stenosis.

A total of 76 patients (1.8%) had a clinically definitive stroke following surgery. Of those, 18 patients had significant carotid stenosis (23.7%). Although stroke was more common in individuals with carotid stenosis than in those without (7.5% vs 1.8%), 14 of the 18 strokes “occurred outside the territory of diseased carotid artery,” the study authors noted. Furthermore, the majority (76.3%) of postoperative strokes occurred in individuals without carotid disease, and 60% of the strokes were not confined to a single carotid artery.

“According to clinical data, in 94.7% of patients, stroke occurred without direct correlation to significant carotid stenosis,” the study authors wrote. “This study strongly suggests there is no direct causal relationship between postoperative stroke and severe carotid stenosis.”

In a related editorial, Louis R. Caplan, MD, Professor of Neurology at Harvard Medical School in Boston, commented on the neurologic complications of elective coronary artery surgery. “Processes that include checklists and time-outs during which the team reviews findings and strategies have led to reduced medical errors and improved outcomes,” Dr. Caplan wrote. “I suggest that patients and preoperative information should be reviewed before surgery by a team approach that includes a cardiologist who will observe the patients throughout their hospitalization and the cardiac surgeon who will perform the operation.”
Li Y, Walicki D, Mathiesen C, et al. Strokes after cardiac surgery and relationship to carotid stenosis. Arch Neurol. 2009;66(9):1091-1096.
Caplan LR. Translating what is known about neurological complications of coronary artery bypass graft surgery into action. Arch Neurol. 2009;66(9):1062-1064.

CT Scans in Children With Head Injury
Researchers have identified guidelines for accurately predicting children at very low risk of clinically important traumatic brain injuries (TBI), for whom CT scans should be avoided, as reported in the September 15 online Lancet. Nathan Kuppermann, MD, of the University of California-Davis School of Medicine in Sacramento, and colleagues analyzed 42,412 children with head trauma in 25 North American emergency departments, and derived and validated age-specific prediction rules for clinically important TBI. Application of these rules, the investigators believe, could limit CT use, protecting children from unnecessary radiation risks.

Dr. Kuppermann’s group, the Pediatric Emergency Care Applied Research Network, identified the following algorithms with 100% and 99.95% negative predictive value for clinically important TBI, respectively:

• For children younger than 2, normal mental status, no scalp hematoma except frontal, no loss of consciousness or loss of consciousness for less than 5 seconds, nonsevere injury mechanism, no palpable skull fracture, and acting normally according to the parents.
• For children 2 and older, normal mental status, no loss of consciousness, no vomiting, nonsevere injury mechanism, no signs of basilar skull fracture, and no severe headache.

“Data to guide clinical decision making for children with head trauma are urgently needed because head trauma is common and CT use is increasing,” the study authors commented. “Children sustaining minor head trauma infrequently have TBI and rarely need neurosurgery. The small risk of clinically important TBI should be balanced against the risks of ionizing radiation of CTs.”

“Kuppermann and colleagues remind us that the rules are meant to inform clinical decision making, not to replace it,” Patricia C. Parkin, MD, and Jonathon L. Maguire, MD, of the Division of Pediatric Medicine and the Pediatric Outcomes Research Team at the Hospital for Sick Children in Toronto, wrote in an accompanying comment. “The next challenge for evidence-based medicine is knowledge translation. Decision aids might provide structured presentations of options and outcomes.”
Kuppermann N, Holmes JF, Dayan PS, et al. Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet. 2009 Sep 14; [Epub ahead of print].
Parkin PC, Maguire JL. Clinically important head injuries after head trauma in children. Lancet. 2009 Sep 14; [Epub ahead of print].

Parent-of-Origin Effects in MS
The greater female-to-male ratio in patients with multiple sclerosis (MS) appears to be more strongly related to the mother, a study published in the August 25 Neurology reported. This maternal parent-of-origin effect, previously seen in studies of half-siblings and avuncular pairs, was found in offspring from a Caucasian mother and North American Aboriginal father.

S.V. Ramagopalan, DPhil, of the Wellcome Trust Centre for Human Genetics at the University of Oxford, UK, and colleagues examined 30,000 MS cases from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) and identified 58 individuals with one Caucasian parent and one North American Aboriginal parent. Of these, 27 had a Caucasian mother and 31 had a North American Aboriginal mother. Although the total number of affected offspring was similar in the two mating types studied, the sex ratio differed. Female-to-male sex ratio was 7:1 for patients with MS who had a Caucasian mother, compared with a 2:1 ratio for those with a Caucasian father.

“A parent-of-origin effect (maternal) has been repeatedly observed in MS, based on studies of half-siblings, sibships including dizygotic twins, a large extended Dutch pedigree, and avuncular pairs, as well as timing of birth effect,” the study authors noted. “The comparison of offspring from interracial matings is a novel method of analysis to look for parent of origin effects.

“The data from this study hint at an intriguing possibility that the observed female preponderance of MS could result from environmental factors acting upon mothers to differentially affect MS risk more in female than in male offspring,” the researchers pointed out.

In a related editorial, John W. Rose, MD, commented that this study “illustrated the continued potential of the CCPGSMS to address interesting questions related to the disease.… By evaluating a small set of MS patients with a Caucasian parent and a Native Aboriginal American parent, the investigators were able to assess parental effects on the disease,” he continued. “The susceptibility to disease is presumed to be predominantly introduced by the Caucasian parent based on previous investigations. In this admixture study, the results demonstrate a maternal effect which strongly influences the sex ratio of offspring affected by MS, linking these two classes of gender differences in MS.”
Ramagopalan SV, Yee IM, Dyment DA, et al. Parent-of-origin effect in multiple sclerosis: observations from interracial matings. Neurology. 2009;73(8):602-605.
Rose JW. Multiple sclerosis: evidence of maternal effects and an increasing incidence in women. Neurology. 2009;73(8):578-579.

Stroke After Cardiac Surgery and Role of Carotid Stenosis
Combining carotid and cardiac procedures is neither necessary nor effective in reducing postoperative stroke in patients with asymptomatic carotid stenosis, according to a study in the September Archives of Neurology. Researchers found no direct causal relationship between significant carotid stenosis and postoperative stroke in patients who underwent cardiac operations.

Yuebing Li, MD, PhD, and colleagues at Lehigh Valley Hospital and Health Network in Allentown, Pennsylvania, reviewed data of 4,335 patients receiving nonurgent coronary artery bypass grafting (CABG) and/or aortic valve replacement between July 2001 and December 2006. Prior to surgery, 3,942 patients were evaluated for carotid stenosis using high-resolution sonography, 239 (6.1%) of whom were identified as having significant carotid stenosis.

A total of 76 patients (1.8%) had a clinically definitive stroke following surgery. Of those, 18 patients had significant carotid stenosis (23.7%). Although stroke was more common in individuals with carotid stenosis than in those without (7.5% vs 1.8%), 14 of the 18 strokes “occurred outside the territory of diseased carotid artery,” the study authors noted. Furthermore, the majority (76.3%) of postoperative strokes occurred in individuals without carotid disease, and 60% of the strokes were not confined to a single carotid artery.

“According to clinical data, in 94.7% of patients, stroke occurred without direct correlation to significant carotid stenosis,” the study authors wrote. “This study strongly suggests there is no direct causal relationship between postoperative stroke and severe carotid stenosis.”

In a related editorial, Louis R. Caplan, MD, Professor of Neurology at Harvard Medical School in Boston, commented on the neurologic complications of elective coronary artery surgery. “Processes that include checklists and time-outs during which the team reviews findings and strategies have led to reduced medical errors and improved outcomes,” Dr. Caplan wrote. “I suggest that patients and preoperative information should be reviewed before surgery by a team approach that includes a cardiologist who will observe the patients throughout their hospitalization and the cardiac surgeon who will perform the operation.”
Li Y, Walicki D, Mathiesen C, et al. Strokes after cardiac surgery and relationship to carotid stenosis. Arch Neurol. 2009;66(9):1091-1096.
Caplan LR. Translating what is known about neurological complications of coronary artery bypass graft surgery into action. Arch Neurol. 2009;66(9):1062-1064.

CT Scans in Children With Head Injury
Researchers have identified guidelines for accurately predicting children at very low risk of clinically important traumatic brain injuries (TBI), for whom CT scans should be avoided, as reported in the September 15 online Lancet. Nathan Kuppermann, MD, of the University of California-Davis School of Medicine in Sacramento, and colleagues analyzed 42,412 children with head trauma in 25 North American emergency departments, and derived and validated age-specific prediction rules for clinically important TBI. Application of these rules, the investigators believe, could limit CT use, protecting children from unnecessary radiation risks.

Dr. Kuppermann’s group, the Pediatric Emergency Care Applied Research Network, identified the following algorithms with 100% and 99.95% negative predictive value for clinically important TBI, respectively:

• For children younger than 2, normal mental status, no scalp hematoma except frontal, no loss of consciousness or loss of consciousness for less than 5 seconds, nonsevere injury mechanism, no palpable skull fracture, and acting normally according to the parents.
• For children 2 and older, normal mental status, no loss of consciousness, no vomiting, nonsevere injury mechanism, no signs of basilar skull fracture, and no severe headache.

“Data to guide clinical decision making for children with head trauma are urgently needed because head trauma is common and CT use is increasing,” the study authors commented. “Children sustaining minor head trauma infrequently have TBI and rarely need neurosurgery. The small risk of clinically important TBI should be balanced against the risks of ionizing radiation of CTs.”

“Kuppermann and colleagues remind us that the rules are meant to inform clinical decision making, not to replace it,” Patricia C. Parkin, MD, and Jonathon L. Maguire, MD, of the Division of Pediatric Medicine and the Pediatric Outcomes Research Team at the Hospital for Sick Children in Toronto, wrote in an accompanying comment. “The next challenge for evidence-based medicine is knowledge translation. Decision aids might provide structured presentations of options and outcomes.”
Kuppermann N, Holmes JF, Dayan PS, et al. Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet. 2009 Sep 14; [Epub ahead of print].
Parkin PC, Maguire JL. Clinically important head injuries after head trauma in children. Lancet. 2009 Sep 14; [Epub ahead of print].

Parent-of-Origin Effects in MS
The greater female-to-male ratio in patients with multiple sclerosis (MS) appears to be more strongly related to the mother, a study published in the August 25 Neurology reported. This maternal parent-of-origin effect, previously seen in studies of half-siblings and avuncular pairs, was found in offspring from a Caucasian mother and North American Aboriginal father.

S.V. Ramagopalan, DPhil, of the Wellcome Trust Centre for Human Genetics at the University of Oxford, UK, and colleagues examined 30,000 MS cases from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) and identified 58 individuals with one Caucasian parent and one North American Aboriginal parent. Of these, 27 had a Caucasian mother and 31 had a North American Aboriginal mother. Although the total number of affected offspring was similar in the two mating types studied, the sex ratio differed. Female-to-male sex ratio was 7:1 for patients with MS who had a Caucasian mother, compared with a 2:1 ratio for those with a Caucasian father.

“A parent-of-origin effect (maternal) has been repeatedly observed in MS, based on studies of half-siblings, sibships including dizygotic twins, a large extended Dutch pedigree, and avuncular pairs, as well as timing of birth effect,” the study authors noted. “The comparison of offspring from interracial matings is a novel method of analysis to look for parent of origin effects.

“The data from this study hint at an intriguing possibility that the observed female preponderance of MS could result from environmental factors acting upon mothers to differentially affect MS risk more in female than in male offspring,” the researchers pointed out.

In a related editorial, John W. Rose, MD, commented that this study “illustrated the continued potential of the CCPGSMS to address interesting questions related to the disease.… By evaluating a small set of MS patients with a Caucasian parent and a Native Aboriginal American parent, the investigators were able to assess parental effects on the disease,” he continued. “The susceptibility to disease is presumed to be predominantly introduced by the Caucasian parent based on previous investigations. In this admixture study, the results demonstrate a maternal effect which strongly influences the sex ratio of offspring affected by MS, linking these two classes of gender differences in MS.”
Ramagopalan SV, Yee IM, Dyment DA, et al. Parent-of-origin effect in multiple sclerosis: observations from interracial matings. Neurology. 2009;73(8):602-605.
Rose JW. Multiple sclerosis: evidence of maternal effects and an increasing incidence in women. Neurology. 2009;73(8):578-579.

Stroke After Cardiac Surgery and Role of Carotid Stenosis
Combining carotid and cardiac procedures is neither necessary nor effective in reducing postoperative stroke in patients with asymptomatic carotid stenosis, according to a study in the September Archives of Neurology. Researchers found no direct causal relationship between significant carotid stenosis and postoperative stroke in patients who underwent cardiac operations.

Yuebing Li, MD, PhD, and colleagues at Lehigh Valley Hospital and Health Network in Allentown, Pennsylvania, reviewed data of 4,335 patients receiving nonurgent coronary artery bypass grafting (CABG) and/or aortic valve replacement between July 2001 and December 2006. Prior to surgery, 3,942 patients were evaluated for carotid stenosis using high-resolution sonography, 239 (6.1%) of whom were identified as having significant carotid stenosis.

A total of 76 patients (1.8%) had a clinically definitive stroke following surgery. Of those, 18 patients had significant carotid stenosis (23.7%). Although stroke was more common in individuals with carotid stenosis than in those without (7.5% vs 1.8%), 14 of the 18 strokes “occurred outside the territory of diseased carotid artery,” the study authors noted. Furthermore, the majority (76.3%) of postoperative strokes occurred in individuals without carotid disease, and 60% of the strokes were not confined to a single carotid artery.

“According to clinical data, in 94.7% of patients, stroke occurred without direct correlation to significant carotid stenosis,” the study authors wrote. “This study strongly suggests there is no direct causal relationship between postoperative stroke and severe carotid stenosis.”

In a related editorial, Louis R. Caplan, MD, Professor of Neurology at Harvard Medical School in Boston, commented on the neurologic complications of elective coronary artery surgery. “Processes that include checklists and time-outs during which the team reviews findings and strategies have led to reduced medical errors and improved outcomes,” Dr. Caplan wrote. “I suggest that patients and preoperative information should be reviewed before surgery by a team approach that includes a cardiologist who will observe the patients throughout their hospitalization and the cardiac surgeon who will perform the operation.”
Li Y, Walicki D, Mathiesen C, et al. Strokes after cardiac surgery and relationship to carotid stenosis. Arch Neurol. 2009;66(9):1091-1096.
Caplan LR. Translating what is known about neurological complications of coronary artery bypass graft surgery into action. Arch Neurol. 2009;66(9):1062-1064.

CT Scans in Children With Head Injury
Researchers have identified guidelines for accurately predicting children at very low risk of clinically important traumatic brain injuries (TBI), for whom CT scans should be avoided, as reported in the September 15 online Lancet. Nathan Kuppermann, MD, of the University of California-Davis School of Medicine in Sacramento, and colleagues analyzed 42,412 children with head trauma in 25 North American emergency departments, and derived and validated age-specific prediction rules for clinically important TBI. Application of these rules, the investigators believe, could limit CT use, protecting children from unnecessary radiation risks.

Dr. Kuppermann’s group, the Pediatric Emergency Care Applied Research Network, identified the following algorithms with 100% and 99.95% negative predictive value for clinically important TBI, respectively:

• For children younger than 2, normal mental status, no scalp hematoma except frontal, no loss of consciousness or loss of consciousness for less than 5 seconds, nonsevere injury mechanism, no palpable skull fracture, and acting normally according to the parents.
• For children 2 and older, normal mental status, no loss of consciousness, no vomiting, nonsevere injury mechanism, no signs of basilar skull fracture, and no severe headache.

“Data to guide clinical decision making for children with head trauma are urgently needed because head trauma is common and CT use is increasing,” the study authors commented. “Children sustaining minor head trauma infrequently have TBI and rarely need neurosurgery. The small risk of clinically important TBI should be balanced against the risks of ionizing radiation of CTs.”

“Kuppermann and colleagues remind us that the rules are meant to inform clinical decision making, not to replace it,” Patricia C. Parkin, MD, and Jonathon L. Maguire, MD, of the Division of Pediatric Medicine and the Pediatric Outcomes Research Team at the Hospital for Sick Children in Toronto, wrote in an accompanying comment. “The next challenge for evidence-based medicine is knowledge translation. Decision aids might provide structured presentations of options and outcomes.”
Kuppermann N, Holmes JF, Dayan PS, et al. Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet. 2009 Sep 14; [Epub ahead of print].
Parkin PC, Maguire JL. Clinically important head injuries after head trauma in children. Lancet. 2009 Sep 14; [Epub ahead of print].

Parent-of-Origin Effects in MS
The greater female-to-male ratio in patients with multiple sclerosis (MS) appears to be more strongly related to the mother, a study published in the August 25 Neurology reported. This maternal parent-of-origin effect, previously seen in studies of half-siblings and avuncular pairs, was found in offspring from a Caucasian mother and North American Aboriginal father.

S.V. Ramagopalan, DPhil, of the Wellcome Trust Centre for Human Genetics at the University of Oxford, UK, and colleagues examined 30,000 MS cases from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) and identified 58 individuals with one Caucasian parent and one North American Aboriginal parent. Of these, 27 had a Caucasian mother and 31 had a North American Aboriginal mother. Although the total number of affected offspring was similar in the two mating types studied, the sex ratio differed. Female-to-male sex ratio was 7:1 for patients with MS who had a Caucasian mother, compared with a 2:1 ratio for those with a Caucasian father.

“A parent-of-origin effect (maternal) has been repeatedly observed in MS, based on studies of half-siblings, sibships including dizygotic twins, a large extended Dutch pedigree, and avuncular pairs, as well as timing of birth effect,” the study authors noted. “The comparison of offspring from interracial matings is a novel method of analysis to look for parent of origin effects.

“The data from this study hint at an intriguing possibility that the observed female preponderance of MS could result from environmental factors acting upon mothers to differentially affect MS risk more in female than in male offspring,” the researchers pointed out.

In a related editorial, John W. Rose, MD, commented that this study “illustrated the continued potential of the CCPGSMS to address interesting questions related to the disease.… By evaluating a small set of MS patients with a Caucasian parent and a Native Aboriginal American parent, the investigators were able to assess parental effects on the disease,” he continued. “The susceptibility to disease is presumed to be predominantly introduced by the Caucasian parent based on previous investigations. In this admixture study, the results demonstrate a maternal effect which strongly influences the sex ratio of offspring affected by MS, linking these two classes of gender differences in MS.”
Ramagopalan SV, Yee IM, Dyment DA, et al. Parent-of-origin effect in multiple sclerosis: observations from interracial matings. Neurology. 2009;73(8):602-605.
Rose JW. Multiple sclerosis: evidence of maternal effects and an increasing incidence in women. Neurology. 2009;73(8):578-579.

—Alina Rabinovich, MD, MS Fellow, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark

Multiple sclerosis (MS) is an autoimmune condition in which autoreactive T cells cross the blood-brain barrier and attack the CNS, causing demyelination and axonal damage. Natalizumab, the newest medication approved for relapsing-remitting MS, is a humanized monoclonal antibody that binds to alpha-4 integrin molecule and prevents T and B cells from entering the brain, thereby decreasing inflammation and thus CNS damage. It has shown great promise in two large-scale multicenter trials with proven effectiveness in decreasing disease relapse rate, as well as accumulation of disability. In general, natalizumab has been well tolerated. Liver abnormalities, allergic reactions, and fatigue are some of its mild side-effects. However, occurrence of progressive multifocal leukoencephalopathy (PML) among patients using natalizumab as part of combination treatment or as monotherapy has caused considerable apprehension among patients and health care professionals about its safety.

PML is a devastating but rare opportunistic viral infection, caused by the JC virus, seen most commonly in patients with HIV, leukemia, and organ transplantation. A novel presentation of PML in MS emerged as a result of natalizumab. Some of the proposed mechanisms are compromised brain immunosurveillance versus mobilization of bone marrow cells carrying the JC virus. Due to surfacing of this infection, natalizumab was taken off the market in 2005. However, careful risk-benefit analysis and studies showing a much greater health gain over the risk of developing PML allowed the drug to be reapproved by the FDA in 2006. Proper use is mandated, such that it is used primarily as a second-line agent in patients with relapsing forms of MS, close clinical surveillance of patients is maintained, and it remains a monotherapy only, as using it in combination with other immunosuppressive agents may greatly increase chances of opportunistic infections, especially PML.

To date, 14 cases of PML have been reported, with the last two published in the New England Journal of Medicine in September. All cases occurred after 12 or more months of treatment, and the majority of cases occurred after 14 months. It appears that natalizumab is very safe for the first year, with the risk of developing PML increasing thereafter. The overall risk of PML after the first 12-month period of treatment with natalizumab appears to be approximately one in 2,000 to 3,000, given the limited information we have available to date. The key is to use natalizumab correctly and with appropriate surveillance. Close patient observation and clinical vigilance are necessary for early detection of PML. As the diagnosis is made early, the drug discontinued and residual drug removed by plasmapheresis, some patients have done well despite the potential deleterious effects of immune reconstitution syndrome on the brain as the virus is eliminated. Patients must be informed that individual susceptibility is not known, and regular laboratory surveillance of the JC virus in the blood and urine is of limited use with current techniques. Therefore, clear risk assessment is difficult at this time. Each patient must be clearly informed of the symptoms of PML. In the future, ongoing analysis will clarify the true safety profile of natalizumab and better define its role in the treatment of MS.

—Alina Rabinovich, MD, MS Fellow, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark

Multiple sclerosis (MS) is an autoimmune condition in which autoreactive T cells cross the blood-brain barrier and attack the CNS, causing demyelination and axonal damage. Natalizumab, the newest medication approved for relapsing-remitting MS, is a humanized monoclonal antibody that binds to alpha-4 integrin molecule and prevents T and B cells from entering the brain, thereby decreasing inflammation and thus CNS damage. It has shown great promise in two large-scale multicenter trials with proven effectiveness in decreasing disease relapse rate, as well as accumulation of disability. In general, natalizumab has been well tolerated. Liver abnormalities, allergic reactions, and fatigue are some of its mild side-effects. However, occurrence of progressive multifocal leukoencephalopathy (PML) among patients using natalizumab as part of combination treatment or as monotherapy has caused considerable apprehension among patients and health care professionals about its safety.

PML is a devastating but rare opportunistic viral infection, caused by the JC virus, seen most commonly in patients with HIV, leukemia, and organ transplantation. A novel presentation of PML in MS emerged as a result of natalizumab. Some of the proposed mechanisms are compromised brain immunosurveillance versus mobilization of bone marrow cells carrying the JC virus. Due to surfacing of this infection, natalizumab was taken off the market in 2005. However, careful risk-benefit analysis and studies showing a much greater health gain over the risk of developing PML allowed the drug to be reapproved by the FDA in 2006. Proper use is mandated, such that it is used primarily as a second-line agent in patients with relapsing forms of MS, close clinical surveillance of patients is maintained, and it remains a monotherapy only, as using it in combination with other immunosuppressive agents may greatly increase chances of opportunistic infections, especially PML.

To date, 14 cases of PML have been reported, with the last two published in the New England Journal of Medicine in September. All cases occurred after 12 or more months of treatment, and the majority of cases occurred after 14 months. It appears that natalizumab is very safe for the first year, with the risk of developing PML increasing thereafter. The overall risk of PML after the first 12-month period of treatment with natalizumab appears to be approximately one in 2,000 to 3,000, given the limited information we have available to date. The key is to use natalizumab correctly and with appropriate surveillance. Close patient observation and clinical vigilance are necessary for early detection of PML. As the diagnosis is made early, the drug discontinued and residual drug removed by plasmapheresis, some patients have done well despite the potential deleterious effects of immune reconstitution syndrome on the brain as the virus is eliminated. Patients must be informed that individual susceptibility is not known, and regular laboratory surveillance of the JC virus in the blood and urine is of limited use with current techniques. Therefore, clear risk assessment is difficult at this time. Each patient must be clearly informed of the symptoms of PML. In the future, ongoing analysis will clarify the true safety profile of natalizumab and better define its role in the treatment of MS.

—Alina Rabinovich, MD, MS Fellow, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark

Multiple sclerosis (MS) is an autoimmune condition in which autoreactive T cells cross the blood-brain barrier and attack the CNS, causing demyelination and axonal damage. Natalizumab, the newest medication approved for relapsing-remitting MS, is a humanized monoclonal antibody that binds to alpha-4 integrin molecule and prevents T and B cells from entering the brain, thereby decreasing inflammation and thus CNS damage. It has shown great promise in two large-scale multicenter trials with proven effectiveness in decreasing disease relapse rate, as well as accumulation of disability. In general, natalizumab has been well tolerated. Liver abnormalities, allergic reactions, and fatigue are some of its mild side-effects. However, occurrence of progressive multifocal leukoencephalopathy (PML) among patients using natalizumab as part of combination treatment or as monotherapy has caused considerable apprehension among patients and health care professionals about its safety.

PML is a devastating but rare opportunistic viral infection, caused by the JC virus, seen most commonly in patients with HIV, leukemia, and organ transplantation. A novel presentation of PML in MS emerged as a result of natalizumab. Some of the proposed mechanisms are compromised brain immunosurveillance versus mobilization of bone marrow cells carrying the JC virus. Due to surfacing of this infection, natalizumab was taken off the market in 2005. However, careful risk-benefit analysis and studies showing a much greater health gain over the risk of developing PML allowed the drug to be reapproved by the FDA in 2006. Proper use is mandated, such that it is used primarily as a second-line agent in patients with relapsing forms of MS, close clinical surveillance of patients is maintained, and it remains a monotherapy only, as using it in combination with other immunosuppressive agents may greatly increase chances of opportunistic infections, especially PML.

To date, 14 cases of PML have been reported, with the last two published in the New England Journal of Medicine in September. All cases occurred after 12 or more months of treatment, and the majority of cases occurred after 14 months. It appears that natalizumab is very safe for the first year, with the risk of developing PML increasing thereafter. The overall risk of PML after the first 12-month period of treatment with natalizumab appears to be approximately one in 2,000 to 3,000, given the limited information we have available to date. The key is to use natalizumab correctly and with appropriate surveillance. Close patient observation and clinical vigilance are necessary for early detection of PML. As the diagnosis is made early, the drug discontinued and residual drug removed by plasmapheresis, some patients have done well despite the potential deleterious effects of immune reconstitution syndrome on the brain as the virus is eliminated. Patients must be informed that individual susceptibility is not known, and regular laboratory surveillance of the JC virus in the blood and urine is of limited use with current techniques. Therefore, clear risk assessment is difficult at this time. Each patient must be clearly informed of the symptoms of PML. In the future, ongoing analysis will clarify the true safety profile of natalizumab and better define its role in the treatment of MS.

Subclinical reactivation of a virus that causes progressive multifocal leukoencephalopathy (PML) occurs frequently in patients with multiple sclerosis (MS) who use natalizumab, according to a study in the September 10 issue of theNew England Journal of Medicine. In 2005, the drug was briefly taken off the market due to a potential link with PML and was reinstated in 2006 after further testing.

PML is induced by the JC virus, a typically dormant virus that is present in urine, but not blood, samples of about one-third of healthy adults. In immune compromised patients, such as those with leukemia or AIDS, the virus can cross into the bloodstream and travel to the brain, causing PML.

Asymptomatic Reactivation of the JC Virus Is Observed

Igor Koralnik, MD, of the Department of Neurology and Division of Viral Pathogenesis at Beth Israel Deaconess Medical Center, and Associate Professor of Neurology at Harvard Medical School in Boston, and colleagues included 19 patients (15 women; median age, 42; median disease duration, five years) who were treated with natalizumab at the MS Clinic of Beth Israel Deaconess Medical Center Neurology Department in Boston. Urine and blood samples were collected and tested for the JC virus at the start of treatment and again at three, six, 12, and 18 months.

At study onset, three of 16 patients’ urine samples tested positive for the JC virus, and all blood samples were negative. At 12 months, 12 of 19 (63%) patients tested positive in urine samples, and one tested positive in blood samples. At the end of the study, researchers found evidence of the JC virus in three of 15 plasma samples (20%) and in nine of 15 samples of peripheral-blood mononuclear cells (60%). In addition, no patients had a neurologic deficit or new brain lesions consistent with PML during the study.

Thorough Monitoring Is Recommended

“The frequency of JC viremia reached in our patients with MS who were treated with natalizumab was higher than that observed in patients infected with HIV and similar only to that seen in patients with PML,” Dr. Koralnik and colleagues reported. “Viremia followed the increase in viruria. Therefore, the initial site of JC virus reactivation may have been the kidney, owing perhaps to decreased immunosurveillance in this compartment caused by natalizumab, which led to a secondary spread of virus to hematopoietic sites and to the subsequent release of JC virus-infected cells into the bloodstream.

“Our findings suggest that monitoring for JC virus in the urine of patients receiving natalizumab therapy and also, after 18 months, in peripheral-blood mononuclear cells in patients with viruria could provide some insight into viral replication,” the study authors commented.

“It is possible that natalizumab has a direct negative effect on JC virus–specific T cells occurring at around one year of treatment, which may have participated in JC virus reactivation in the kidney and its subsequent spread into the blood,” Dr. Chen’s group concluded.

—Rebecca K. Abma

Subclinical reactivation of a virus that causes progressive multifocal leukoencephalopathy (PML) occurs frequently in patients with multiple sclerosis (MS) who use natalizumab, according to a study in the September 10 issue of theNew England Journal of Medicine. In 2005, the drug was briefly taken off the market due to a potential link with PML and was reinstated in 2006 after further testing.

PML is induced by the JC virus, a typically dormant virus that is present in urine, but not blood, samples of about one-third of healthy adults. In immune compromised patients, such as those with leukemia or AIDS, the virus can cross into the bloodstream and travel to the brain, causing PML.

Asymptomatic Reactivation of the JC Virus Is Observed

Igor Koralnik, MD, of the Department of Neurology and Division of Viral Pathogenesis at Beth Israel Deaconess Medical Center, and Associate Professor of Neurology at Harvard Medical School in Boston, and colleagues included 19 patients (15 women; median age, 42; median disease duration, five years) who were treated with natalizumab at the MS Clinic of Beth Israel Deaconess Medical Center Neurology Department in Boston. Urine and blood samples were collected and tested for the JC virus at the start of treatment and again at three, six, 12, and 18 months.

At study onset, three of 16 patients’ urine samples tested positive for the JC virus, and all blood samples were negative. At 12 months, 12 of 19 (63%) patients tested positive in urine samples, and one tested positive in blood samples. At the end of the study, researchers found evidence of the JC virus in three of 15 plasma samples (20%) and in nine of 15 samples of peripheral-blood mononuclear cells (60%). In addition, no patients had a neurologic deficit or new brain lesions consistent with PML during the study.

Thorough Monitoring Is Recommended

“The frequency of JC viremia reached in our patients with MS who were treated with natalizumab was higher than that observed in patients infected with HIV and similar only to that seen in patients with PML,” Dr. Koralnik and colleagues reported. “Viremia followed the increase in viruria. Therefore, the initial site of JC virus reactivation may have been the kidney, owing perhaps to decreased immunosurveillance in this compartment caused by natalizumab, which led to a secondary spread of virus to hematopoietic sites and to the subsequent release of JC virus-infected cells into the bloodstream.

“Our findings suggest that monitoring for JC virus in the urine of patients receiving natalizumab therapy and also, after 18 months, in peripheral-blood mononuclear cells in patients with viruria could provide some insight into viral replication,” the study authors commented.

“It is possible that natalizumab has a direct negative effect on JC virus–specific T cells occurring at around one year of treatment, which may have participated in JC virus reactivation in the kidney and its subsequent spread into the blood,” Dr. Chen’s group concluded.

—Rebecca K. Abma

Subclinical reactivation of a virus that causes progressive multifocal leukoencephalopathy (PML) occurs frequently in patients with multiple sclerosis (MS) who use natalizumab, according to a study in the September 10 issue of theNew England Journal of Medicine. In 2005, the drug was briefly taken off the market due to a potential link with PML and was reinstated in 2006 after further testing.

PML is induced by the JC virus, a typically dormant virus that is present in urine, but not blood, samples of about one-third of healthy adults. In immune compromised patients, such as those with leukemia or AIDS, the virus can cross into the bloodstream and travel to the brain, causing PML.

Asymptomatic Reactivation of the JC Virus Is Observed

Igor Koralnik, MD, of the Department of Neurology and Division of Viral Pathogenesis at Beth Israel Deaconess Medical Center, and Associate Professor of Neurology at Harvard Medical School in Boston, and colleagues included 19 patients (15 women; median age, 42; median disease duration, five years) who were treated with natalizumab at the MS Clinic of Beth Israel Deaconess Medical Center Neurology Department in Boston. Urine and blood samples were collected and tested for the JC virus at the start of treatment and again at three, six, 12, and 18 months.

At study onset, three of 16 patients’ urine samples tested positive for the JC virus, and all blood samples were negative. At 12 months, 12 of 19 (63%) patients tested positive in urine samples, and one tested positive in blood samples. At the end of the study, researchers found evidence of the JC virus in three of 15 plasma samples (20%) and in nine of 15 samples of peripheral-blood mononuclear cells (60%). In addition, no patients had a neurologic deficit or new brain lesions consistent with PML during the study.

Thorough Monitoring Is Recommended

“The frequency of JC viremia reached in our patients with MS who were treated with natalizumab was higher than that observed in patients infected with HIV and similar only to that seen in patients with PML,” Dr. Koralnik and colleagues reported. “Viremia followed the increase in viruria. Therefore, the initial site of JC virus reactivation may have been the kidney, owing perhaps to decreased immunosurveillance in this compartment caused by natalizumab, which led to a secondary spread of virus to hematopoietic sites and to the subsequent release of JC virus-infected cells into the bloodstream.

“Our findings suggest that monitoring for JC virus in the urine of patients receiving natalizumab therapy and also, after 18 months, in peripheral-blood mononuclear cells in patients with viruria could provide some insight into viral replication,” the study authors commented.

“It is possible that natalizumab has a direct negative effect on JC virus–specific T cells occurring at around one year of treatment, which may have participated in JC virus reactivation in the kidney and its subsequent spread into the blood,” Dr. Chen’s group concluded.

—Rebecca K. Abma

Higher diastolic blood pressure (DBP) is cross-sectionally and independently associated with cognitive impairment, investigators reported in the August 25 Neurology. The association was found after adjusting for economic factors, depressive symptoms, and current use of any antihyperintensive medication in 30,228 black and white men and women (45 and older). “An increment of 10 mm Hg in DBP was associated with a 7% higher odds of cognitive impairment,” the researchers stated. “No independent association was identified between impaired cognitive status and systolic blood pressure (odds ratio [OR], 1.02) or pulse pressure (OR, 0.99).” No evidence of nonlinear relationships between any blood pressure components and impaired cognitive status was found.

Use of smokeless tobacco products is associated with risk of fatal myocardial infarction and stroke, according to the August 18 online BMJ. Investigators from Sweden and the United States conducted a meta-analysis of 11 observational studies (primarily including men). “Eight risk estimates were available for fatal myocardial infarction: the relative risk for ever use of smokeless tobacco products was 1.13 and the excess risk was restricted to current users,” the investigators stated. “The relative risk of fatal stroke, on the basis of five risk estimates, was 1.40.” Increased risk of fatal myocardial infarction was shown in studies from both geographic locations. “Data on dose-response were limited but did not suggest a strong relation between risk of dying from either disease and frequency or duration of use of smokeless tobacco products,” the researchers noted.

A mutation in transcriptional repressor hDEC2-P385R is associated with a human short sleep phenotype, according to a study in the August 14 issue of Science. Investigators found that within a small extended family, two members with the mutation had lifelong shorter daily sleep requirements than most persons. The researchers then genetically engineered mice and fruit flies to express the mutated human gene and studied its impact on behavior and sleep patterns. “Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time- and sleep deprivation-dependent manner,” the study authors stated. “These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.”

The FDA has approved Extavia for reducing the frequency of clinical exacerbations in patients with relapsing forms of multiple sclerosis (MS). It is also indicated in patients who have had a first clinical episode of MS and have features consistent with the disease as shown by MRI. Extavia is a new branded version of interferon beta-1b and the same medicinal product as Betaseron. Interferon beta-1b has been shown to reduce annualized relapse rates by 34%, with patients nearly twice as likely to remain relapse-free for more than two years, compared with those receiving placebo. Injection site necrosis has been reported in 4% of patients in controlled trials, and anaphylaxis has been reported as a rare complication of interferon use. Extavia is marketed by the Pharmaceuticals Division of Novartis (East Hanover, NJ) and is expected to be available this fall.

White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (aMCI), and infarcts are more strongly related to nonamnestic MCI, according to a study in the August 11 issue of Neurology. Researchers investigated the relationship of WMH volume and infarcts in brain per MRI to MCI in 679 elderly persons without dementia. WMH was adjusted for total cranial volume, and MCI was defined using the Peterson criteria. WMH was more strongly related to aMCI (OR, 1.9) than nonamnestic MCI (OR, 1.6). However, infarcts were more strongly related to nonamnestic MCI (OR, 2.7) than aMCI (OR, 1.4). “In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with nonamnestic domains,” the researchers noted. “The nature of WMH in aMCI requires further study,” they concluded.

Intellectually normal children with seizures had neuropsychologic deficits at seizure onset, per a study published in the August 18 issue of Neurology. Investigators compared 282 children between ages 6 and 14 who had an IQ of 70 or higher and with a first recognized seizure to 147 healthy siblings. “In this intellectually normal cohort, 27% with just one seizure and up to 40% of those with risk factors exhibited neuropsychologic deficits at or near onset,” the researchers stated. Risk factors included multiple seizures (ie, second unprovoked seizure, odds ratio [OR], 1.96), use of antiepileptic drugs (OR, 2.27), symptomatic/cryptogenic etiology (OR, 2.15), and epileptiform activity on the initial EEG (OR, 1.96). Increased odds for neuropsychologic impairment were associated with absence epilepsy (OR, 2.00).

The H5N1 avian influenza virus may increase the risk for Parkinson’s disease and other neurologic disorders, according to a report in the August 10 online Proceedings of the National Academy of Sciences. In a mouse model, investigators showed that the virus travels from the peripheral nervous system into the CNS to higher levels of the neuroaxis. “In regions infected by H5N1 virus, we observe activation of microglia and alpha-synuclein phosphorylation and aggregation that persists long after resolution of the infection,” the researchers stated. A significant loss in dopaminergic neurons in the substantia nigra pars compacta was also observed, 60 days after infection. “Our results suggest that a pandemic H5N1 pathogen, or other neurotropic influenza virus, could initiate CNS disorders of protein aggregation including Parkinson’s and Alzheimer’s diseases,” the investigators concluded.

The FDA has approved Sabril (vigabatrin) tablets and oral solution for two difficult-to-treat epilepsies. Vigabatrin is indicated as monotherapy for pediatric patients ages 1 month to 2 years with infantile spasms for whom the potential benefits outweigh the potential risk of vision loss, and as adjunctive add-on therapy in adults with refractory complex partial seizures who have not responded to alternative treatments, and for whom the potential benefits outweigh the risk of vision loss. Vigabatrin use has been linked to permanent bilateral concentric visual field constriction in 30% or more of patients that ranges in severity from mild to severe. Vigabatrin is manufactured by Lundbeck, Inc (Deerfield, Illinois).

Compared with women without epilepsy, epileptic seizures during pregnancy increased the risk for low-birth-weight infants, preterm delivery, and small for gestational age by 1.36-fold, 1.63-fold, and 1.37-fold, respectively, according to a study in the August Archives of Neurology. Researchers in Taiwan matched 1,016 women with epilepsy with single births from 2001 to 2003 and who had been diagnosed with epilepsy in the two years prior to index delivery with 8,128 women without chronic disease. The authors then compared women with epilepsy who had seizures during pregnancy to women with epilepsy who did not have seizures and found that the risk of infants being small for gestational age increased most significantly (odds ratio, 1.34) among those who had seizures during pregnancy.

P2X7 receptor antagonist, Brilliant blue G (BBG), reduced spinal cord anatomic damage and improved motor recovery in rats without evident toxicity when administered 15 minutes after injury, researchers reported in the July 28 Proceedings of the National Academy of Sciences. Treatment with BBG, a derivative of a commonly used food color (FD&C blue No. 1) that is used to give M&Ms and Gatorade their blue tint, also directly reduced local activation of astrocytes and microglia, in addition to neutrophil infiltration. “These observations suggest that BBG not only protected spinal cord neurons from purinergic excitotoxicity, but also reduced local inflammatory responses,” investigators stated. “Systemic administration of BBG may thus comprise a readily feasible approach by which to treat spinal cord injury in humans.”

Although angiotensin-converting enzyme (ACE) inhibitors as a class do not appear to be associated with dementia risk or cognitive decline in older, hypertensive (HTN) adults, within-class differences may occur regarding these outcomes, suggests a study in the July 13 Archives of Internal Medicine. Investigators identified 158 cases of dementia among 414 participants who were exposed to ACE inhibitors and 640 who were not. There was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01). “However, centrally active ACE inhibitors were associated with 65% less decline in Modified Mini-Mental State Examination scores per year of exposure, and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20) and greater odds of disability in instrumental activities of daily living (adjusted OR, 1.16), compared with other anti-hypertension drugs,” investigators reported.

Researchers have found an association between the cytochrome P450 (CYP) 2C19*2 variant and diminished platelet response to clopidogrel treatment and poor cardiovascular outcomes, according to a study in the August 26 JAMA. Clopidogrel was administered for seven days to 429 healthy Amish persons. “Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance,” noted the study authors. “The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention.” In addition, those with the variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death in one year of follow-up.

Intramuscular AVI-4658 induces the expression of dystrophin, benefiting patients with Duchenne muscular dystrophy, according to a study in the August 26 online Lancet Neurology. Investigators assessed the safety of AVI-4658.Two patients received 0.09 mg AVI-4658 in 900 µl (0.9%) saline, and five received 0.9 mg AVI-4658 in 900 µl saline. “In randomly chosen sections of treated EDB muscles, the mean intensity of dystrophin staining ranged from 22% to 32% of the mean intensity of dystrophin in healthy control muscles (mean, 26.4%), and the mean intensity was 17% (range, 11% to 21%) greater than the intensity in the contralateral saline-treated muscle,” the researchers stated. “In the dystrophin-positive fibers, the intensity of dystrophin staining was up to 42% of that in healthy muscle.”

Higher diastolic blood pressure (DBP) is cross-sectionally and independently associated with cognitive impairment, investigators reported in the August 25 Neurology. The association was found after adjusting for economic factors, depressive symptoms, and current use of any antihyperintensive medication in 30,228 black and white men and women (45 and older). “An increment of 10 mm Hg in DBP was associated with a 7% higher odds of cognitive impairment,” the researchers stated. “No independent association was identified between impaired cognitive status and systolic blood pressure (odds ratio [OR], 1.02) or pulse pressure (OR, 0.99).” No evidence of nonlinear relationships between any blood pressure components and impaired cognitive status was found.

Use of smokeless tobacco products is associated with risk of fatal myocardial infarction and stroke, according to the August 18 online BMJ. Investigators from Sweden and the United States conducted a meta-analysis of 11 observational studies (primarily including men). “Eight risk estimates were available for fatal myocardial infarction: the relative risk for ever use of smokeless tobacco products was 1.13 and the excess risk was restricted to current users,” the investigators stated. “The relative risk of fatal stroke, on the basis of five risk estimates, was 1.40.” Increased risk of fatal myocardial infarction was shown in studies from both geographic locations. “Data on dose-response were limited but did not suggest a strong relation between risk of dying from either disease and frequency or duration of use of smokeless tobacco products,” the researchers noted.

A mutation in transcriptional repressor hDEC2-P385R is associated with a human short sleep phenotype, according to a study in the August 14 issue of Science. Investigators found that within a small extended family, two members with the mutation had lifelong shorter daily sleep requirements than most persons. The researchers then genetically engineered mice and fruit flies to express the mutated human gene and studied its impact on behavior and sleep patterns. “Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time- and sleep deprivation-dependent manner,” the study authors stated. “These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.”

The FDA has approved Extavia for reducing the frequency of clinical exacerbations in patients with relapsing forms of multiple sclerosis (MS). It is also indicated in patients who have had a first clinical episode of MS and have features consistent with the disease as shown by MRI. Extavia is a new branded version of interferon beta-1b and the same medicinal product as Betaseron. Interferon beta-1b has been shown to reduce annualized relapse rates by 34%, with patients nearly twice as likely to remain relapse-free for more than two years, compared with those receiving placebo. Injection site necrosis has been reported in 4% of patients in controlled trials, and anaphylaxis has been reported as a rare complication of interferon use. Extavia is marketed by the Pharmaceuticals Division of Novartis (East Hanover, NJ) and is expected to be available this fall.

White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (aMCI), and infarcts are more strongly related to nonamnestic MCI, according to a study in the August 11 issue of Neurology. Researchers investigated the relationship of WMH volume and infarcts in brain per MRI to MCI in 679 elderly persons without dementia. WMH was adjusted for total cranial volume, and MCI was defined using the Peterson criteria. WMH was more strongly related to aMCI (OR, 1.9) than nonamnestic MCI (OR, 1.6). However, infarcts were more strongly related to nonamnestic MCI (OR, 2.7) than aMCI (OR, 1.4). “In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with nonamnestic domains,” the researchers noted. “The nature of WMH in aMCI requires further study,” they concluded.

Intellectually normal children with seizures had neuropsychologic deficits at seizure onset, per a study published in the August 18 issue of Neurology. Investigators compared 282 children between ages 6 and 14 who had an IQ of 70 or higher and with a first recognized seizure to 147 healthy siblings. “In this intellectually normal cohort, 27% with just one seizure and up to 40% of those with risk factors exhibited neuropsychologic deficits at or near onset,” the researchers stated. Risk factors included multiple seizures (ie, second unprovoked seizure, odds ratio [OR], 1.96), use of antiepileptic drugs (OR, 2.27), symptomatic/cryptogenic etiology (OR, 2.15), and epileptiform activity on the initial EEG (OR, 1.96). Increased odds for neuropsychologic impairment were associated with absence epilepsy (OR, 2.00).

The H5N1 avian influenza virus may increase the risk for Parkinson’s disease and other neurologic disorders, according to a report in the August 10 online Proceedings of the National Academy of Sciences. In a mouse model, investigators showed that the virus travels from the peripheral nervous system into the CNS to higher levels of the neuroaxis. “In regions infected by H5N1 virus, we observe activation of microglia and alpha-synuclein phosphorylation and aggregation that persists long after resolution of the infection,” the researchers stated. A significant loss in dopaminergic neurons in the substantia nigra pars compacta was also observed, 60 days after infection. “Our results suggest that a pandemic H5N1 pathogen, or other neurotropic influenza virus, could initiate CNS disorders of protein aggregation including Parkinson’s and Alzheimer’s diseases,” the investigators concluded.

The FDA has approved Sabril (vigabatrin) tablets and oral solution for two difficult-to-treat epilepsies. Vigabatrin is indicated as monotherapy for pediatric patients ages 1 month to 2 years with infantile spasms for whom the potential benefits outweigh the potential risk of vision loss, and as adjunctive add-on therapy in adults with refractory complex partial seizures who have not responded to alternative treatments, and for whom the potential benefits outweigh the risk of vision loss. Vigabatrin use has been linked to permanent bilateral concentric visual field constriction in 30% or more of patients that ranges in severity from mild to severe. Vigabatrin is manufactured by Lundbeck, Inc (Deerfield, Illinois).

Compared with women without epilepsy, epileptic seizures during pregnancy increased the risk for low-birth-weight infants, preterm delivery, and small for gestational age by 1.36-fold, 1.63-fold, and 1.37-fold, respectively, according to a study in the August Archives of Neurology. Researchers in Taiwan matched 1,016 women with epilepsy with single births from 2001 to 2003 and who had been diagnosed with epilepsy in the two years prior to index delivery with 8,128 women without chronic disease. The authors then compared women with epilepsy who had seizures during pregnancy to women with epilepsy who did not have seizures and found that the risk of infants being small for gestational age increased most significantly (odds ratio, 1.34) among those who had seizures during pregnancy.

P2X7 receptor antagonist, Brilliant blue G (BBG), reduced spinal cord anatomic damage and improved motor recovery in rats without evident toxicity when administered 15 minutes after injury, researchers reported in the July 28 Proceedings of the National Academy of Sciences. Treatment with BBG, a derivative of a commonly used food color (FD&C blue No. 1) that is used to give M&Ms and Gatorade their blue tint, also directly reduced local activation of astrocytes and microglia, in addition to neutrophil infiltration. “These observations suggest that BBG not only protected spinal cord neurons from purinergic excitotoxicity, but also reduced local inflammatory responses,” investigators stated. “Systemic administration of BBG may thus comprise a readily feasible approach by which to treat spinal cord injury in humans.”

Although angiotensin-converting enzyme (ACE) inhibitors as a class do not appear to be associated with dementia risk or cognitive decline in older, hypertensive (HTN) adults, within-class differences may occur regarding these outcomes, suggests a study in the July 13 Archives of Internal Medicine. Investigators identified 158 cases of dementia among 414 participants who were exposed to ACE inhibitors and 640 who were not. There was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01). “However, centrally active ACE inhibitors were associated with 65% less decline in Modified Mini-Mental State Examination scores per year of exposure, and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20) and greater odds of disability in instrumental activities of daily living (adjusted OR, 1.16), compared with other anti-hypertension drugs,” investigators reported.

Researchers have found an association between the cytochrome P450 (CYP) 2C19*2 variant and diminished platelet response to clopidogrel treatment and poor cardiovascular outcomes, according to a study in the August 26 JAMA. Clopidogrel was administered for seven days to 429 healthy Amish persons. “Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance,” noted the study authors. “The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention.” In addition, those with the variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death in one year of follow-up.

Intramuscular AVI-4658 induces the expression of dystrophin, benefiting patients with Duchenne muscular dystrophy, according to a study in the August 26 online Lancet Neurology. Investigators assessed the safety of AVI-4658.Two patients received 0.09 mg AVI-4658 in 900 µl (0.9%) saline, and five received 0.9 mg AVI-4658 in 900 µl saline. “In randomly chosen sections of treated EDB muscles, the mean intensity of dystrophin staining ranged from 22% to 32% of the mean intensity of dystrophin in healthy control muscles (mean, 26.4%), and the mean intensity was 17% (range, 11% to 21%) greater than the intensity in the contralateral saline-treated muscle,” the researchers stated. “In the dystrophin-positive fibers, the intensity of dystrophin staining was up to 42% of that in healthy muscle.”

Higher diastolic blood pressure (DBP) is cross-sectionally and independently associated with cognitive impairment, investigators reported in the August 25 Neurology. The association was found after adjusting for economic factors, depressive symptoms, and current use of any antihyperintensive medication in 30,228 black and white men and women (45 and older). “An increment of 10 mm Hg in DBP was associated with a 7% higher odds of cognitive impairment,” the researchers stated. “No independent association was identified between impaired cognitive status and systolic blood pressure (odds ratio [OR], 1.02) or pulse pressure (OR, 0.99).” No evidence of nonlinear relationships between any blood pressure components and impaired cognitive status was found.

Use of smokeless tobacco products is associated with risk of fatal myocardial infarction and stroke, according to the August 18 online BMJ. Investigators from Sweden and the United States conducted a meta-analysis of 11 observational studies (primarily including men). “Eight risk estimates were available for fatal myocardial infarction: the relative risk for ever use of smokeless tobacco products was 1.13 and the excess risk was restricted to current users,” the investigators stated. “The relative risk of fatal stroke, on the basis of five risk estimates, was 1.40.” Increased risk of fatal myocardial infarction was shown in studies from both geographic locations. “Data on dose-response were limited but did not suggest a strong relation between risk of dying from either disease and frequency or duration of use of smokeless tobacco products,” the researchers noted.

A mutation in transcriptional repressor hDEC2-P385R is associated with a human short sleep phenotype, according to a study in the August 14 issue of Science. Investigators found that within a small extended family, two members with the mutation had lifelong shorter daily sleep requirements than most persons. The researchers then genetically engineered mice and fruit flies to express the mutated human gene and studied its impact on behavior and sleep patterns. “Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time- and sleep deprivation-dependent manner,” the study authors stated. “These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.”

The FDA has approved Extavia for reducing the frequency of clinical exacerbations in patients with relapsing forms of multiple sclerosis (MS). It is also indicated in patients who have had a first clinical episode of MS and have features consistent with the disease as shown by MRI. Extavia is a new branded version of interferon beta-1b and the same medicinal product as Betaseron. Interferon beta-1b has been shown to reduce annualized relapse rates by 34%, with patients nearly twice as likely to remain relapse-free for more than two years, compared with those receiving placebo. Injection site necrosis has been reported in 4% of patients in controlled trials, and anaphylaxis has been reported as a rare complication of interferon use. Extavia is marketed by the Pharmaceuticals Division of Novartis (East Hanover, NJ) and is expected to be available this fall.

White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (aMCI), and infarcts are more strongly related to nonamnestic MCI, according to a study in the August 11 issue of Neurology. Researchers investigated the relationship of WMH volume and infarcts in brain per MRI to MCI in 679 elderly persons without dementia. WMH was adjusted for total cranial volume, and MCI was defined using the Peterson criteria. WMH was more strongly related to aMCI (OR, 1.9) than nonamnestic MCI (OR, 1.6). However, infarcts were more strongly related to nonamnestic MCI (OR, 2.7) than aMCI (OR, 1.4). “In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with nonamnestic domains,” the researchers noted. “The nature of WMH in aMCI requires further study,” they concluded.

Intellectually normal children with seizures had neuropsychologic deficits at seizure onset, per a study published in the August 18 issue of Neurology. Investigators compared 282 children between ages 6 and 14 who had an IQ of 70 or higher and with a first recognized seizure to 147 healthy siblings. “In this intellectually normal cohort, 27% with just one seizure and up to 40% of those with risk factors exhibited neuropsychologic deficits at or near onset,” the researchers stated. Risk factors included multiple seizures (ie, second unprovoked seizure, odds ratio [OR], 1.96), use of antiepileptic drugs (OR, 2.27), symptomatic/cryptogenic etiology (OR, 2.15), and epileptiform activity on the initial EEG (OR, 1.96). Increased odds for neuropsychologic impairment were associated with absence epilepsy (OR, 2.00).

The H5N1 avian influenza virus may increase the risk for Parkinson’s disease and other neurologic disorders, according to a report in the August 10 online Proceedings of the National Academy of Sciences. In a mouse model, investigators showed that the virus travels from the peripheral nervous system into the CNS to higher levels of the neuroaxis. “In regions infected by H5N1 virus, we observe activation of microglia and alpha-synuclein phosphorylation and aggregation that persists long after resolution of the infection,” the researchers stated. A significant loss in dopaminergic neurons in the substantia nigra pars compacta was also observed, 60 days after infection. “Our results suggest that a pandemic H5N1 pathogen, or other neurotropic influenza virus, could initiate CNS disorders of protein aggregation including Parkinson’s and Alzheimer’s diseases,” the investigators concluded.

The FDA has approved Sabril (vigabatrin) tablets and oral solution for two difficult-to-treat epilepsies. Vigabatrin is indicated as monotherapy for pediatric patients ages 1 month to 2 years with infantile spasms for whom the potential benefits outweigh the potential risk of vision loss, and as adjunctive add-on therapy in adults with refractory complex partial seizures who have not responded to alternative treatments, and for whom the potential benefits outweigh the risk of vision loss. Vigabatrin use has been linked to permanent bilateral concentric visual field constriction in 30% or more of patients that ranges in severity from mild to severe. Vigabatrin is manufactured by Lundbeck, Inc (Deerfield, Illinois).

Compared with women without epilepsy, epileptic seizures during pregnancy increased the risk for low-birth-weight infants, preterm delivery, and small for gestational age by 1.36-fold, 1.63-fold, and 1.37-fold, respectively, according to a study in the August Archives of Neurology. Researchers in Taiwan matched 1,016 women with epilepsy with single births from 2001 to 2003 and who had been diagnosed with epilepsy in the two years prior to index delivery with 8,128 women without chronic disease. The authors then compared women with epilepsy who had seizures during pregnancy to women with epilepsy who did not have seizures and found that the risk of infants being small for gestational age increased most significantly (odds ratio, 1.34) among those who had seizures during pregnancy.

P2X7 receptor antagonist, Brilliant blue G (BBG), reduced spinal cord anatomic damage and improved motor recovery in rats without evident toxicity when administered 15 minutes after injury, researchers reported in the July 28 Proceedings of the National Academy of Sciences. Treatment with BBG, a derivative of a commonly used food color (FD&C blue No. 1) that is used to give M&Ms and Gatorade their blue tint, also directly reduced local activation of astrocytes and microglia, in addition to neutrophil infiltration. “These observations suggest that BBG not only protected spinal cord neurons from purinergic excitotoxicity, but also reduced local inflammatory responses,” investigators stated. “Systemic administration of BBG may thus comprise a readily feasible approach by which to treat spinal cord injury in humans.”

Although angiotensin-converting enzyme (ACE) inhibitors as a class do not appear to be associated with dementia risk or cognitive decline in older, hypertensive (HTN) adults, within-class differences may occur regarding these outcomes, suggests a study in the July 13 Archives of Internal Medicine. Investigators identified 158 cases of dementia among 414 participants who were exposed to ACE inhibitors and 640 who were not. There was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01). “However, centrally active ACE inhibitors were associated with 65% less decline in Modified Mini-Mental State Examination scores per year of exposure, and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20) and greater odds of disability in instrumental activities of daily living (adjusted OR, 1.16), compared with other anti-hypertension drugs,” investigators reported.

Researchers have found an association between the cytochrome P450 (CYP) 2C19*2 variant and diminished platelet response to clopidogrel treatment and poor cardiovascular outcomes, according to a study in the August 26 JAMA. Clopidogrel was administered for seven days to 429 healthy Amish persons. “Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance,” noted the study authors. “The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention.” In addition, those with the variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death in one year of follow-up.

Intramuscular AVI-4658 induces the expression of dystrophin, benefiting patients with Duchenne muscular dystrophy, according to a study in the August 26 online Lancet Neurology. Investigators assessed the safety of AVI-4658.Two patients received 0.09 mg AVI-4658 in 900 µl (0.9%) saline, and five received 0.9 mg AVI-4658 in 900 µl saline. “In randomly chosen sections of treated EDB muscles, the mean intensity of dystrophin staining ranged from 22% to 32% of the mean intensity of dystrophin in healthy control muscles (mean, 26.4%), and the mean intensity was 17% (range, 11% to 21%) greater than the intensity in the contralateral saline-treated muscle,” the researchers stated. “In the dystrophin-positive fibers, the intensity of dystrophin staining was up to 42% of that in healthy muscle.”

ATLANTA—A pair of studies directly comparing the effectiveness of interferon beta and glatiramer acetate for patients with multiple sclerosis (MS) have found contrasting results, which are dependent on the clinical criteria that are being measured.

In one study, interferon beta-1b was more effective than glatiramer acetate in limiting the conversion of newly enhancing lesions and acute black holes to chronic black holes, which are thought to represent irreversible damage in MS, reported Stuart D. Cook, MD, and colleagues in the August 16 online Journal of Neurology, Neurosurgery, and Psychiatry. However, the two-year risk of relapse was significantly lower in patients with MS who used glatiramer acetate than among those who used interferon beta-lb, interferon beta-1a IM, and interferon beta-1a SC, reported Kenneth P. Johnson, MD, and colleagues at the 2009 Joint Meeting of the Consortium of MS Centers and Americas Committee for Treatment and Research in MS.

Chronic Black Holes in MS
Dr. Cook’s group followed 75 patients with relapsing-remitting MS or a clinically isolated syndrome in the ongoing prospective, randomized Betaseron vs Copaxone in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints (BECOME) study. The researchers used monthly 3-Tesla brain MRI scans for up to two years to observe the development and evolution of new black holes in the participants, who were randomized to receive glatiramer acetate or interferon beta-1b.

A total of 1,224 newly enhancing lesions appearing at baseline through 24 months were observed in 61 patients; 767 (62.7%) lesions showed an acute black hole. “The majority of acute black holes were transient and of similar duration by treatment group,” stated Dr. Cook, Professor of Neurosciences, University of Medicine and Dentistry of New Jersey, New Jersey Medical School in Newark, and coauthors. “Black holes are more common in patients with secondary progression than with relapsing-remitting MS and in aggressive than in benign MS.”

Follow-up scans were available for one year or more regarding 571 acute black holes. The investigators found that 103 (18.8%) black holes were still visible 12 or more months after onset and were thus characterized as chronic black holes. About 12% of the 849 newly enhancing lesions with MRI follow-up for one or more years converted to chronic black holes—9.8% with interferon beta-1b and 15.2% with glatiramer acetate. In addition, the conversion rate from acute black holes to chronic black holes was also lower with interferon beta-1b (15.2%) than with glatiramer acetate (21.4%).

“Although we did find a significantly lower conversion rate from newly enhancing lesions to chronic black holes in brain lesions that develop in patients randomized to interferon beta-1b compared to glatiramer acetate, the difference was modest,” Dr. Cook and colleagues reported. “However, this was an unexpected finding because of the widespread belief in the MS field that glatiramer acetate, but not interferon beta-1b, is neuroprotective. The analysis of the primary outcome of BECOME showed no differences by treatment group in brain MRI activity over one year or in new brain lesion formation or annualized relapse rates over two years.

“Although our study of black holes supports the view that extensive repair takes place in the majority of new brain lesions that occur in relapsing-remitting MS patients treated with first-line disease modifying therapies, it remains to be determined whether similar repair takes place in normal appearing white and gray matter and why lesion repair appears to fail over time in many patients and even early on in some patients.”

Dr. Cook noted that patients with MS are usually started on an interferon beta or glatiramer acetate, but “all are effective drugs,” he told Neurology Reviews. “There are advantages and disadvantages of each drug. Patients and physicians need to discuss the options to select the best drug based on efficacy and tolerability. All are very safe.

“As yet, there is insufficient long-term clinical data to support choosing an interferon versus glatiramer acetate. Recent studies support possible MRI benefit of interferons—for example, the REGARD, BEYOND, and BECOME studies.”

Relapse Rates in MS
Dr. Johnson’s group identified 51,162 patients with MS from an administrative claims database. The investigators conducted a series of pair-wise comparisons between patients who used glatiramer acetate and those who used each of the three interferon beta drugs under usual care conditions in the trial, which was not randomized or prospective. Demographic profiles of participants among the four treatment groups were similar, and no differences regarding use of immunomodulators was observed among patients from various geographic regions. Relapse was defined as either 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.

The researchers found that the two-year risk of relapse for patients who had received glatiramer acetate was 5.3%, compared with a rate of 13.5% in those who had received interferon beta-1b. The two-year risk of relapse for those who had taken glatiramer acetate was 5.2%, versus a rate of 10% among those who used interferon beta-1a IM. The two-year risk of relapse was 5.9% in those who had used glatiramer acetate, compared with 10.9% in those who had taken interferon beta-1a SC.

“In this recent comparison of immunomodulators for MS, the two-year risk of relapse was significantly lower for glatiramer acetate than for any of the three interferon beta drugs,” stated Dr. Johnson, Professor Emeritus of Neurology, University of Maryland, and Program Director of the Maryland Center for MS in Baltimore. “Nationwide outcomes came from treating physicians’ personal treatment decisions, free of drug company–sponsored studies or programs.”

In an interview with Neurology Reviews, Dr. Johnson said, “[Our] data show that in the broad population of patients across the US, glatiramer acetate works better than any of the interferons and is less costly, but it doesn’t work in every patient. We’re just now beginning to figure out which patients respond to which drugs.

“My recommendation,” advised Dr. Johnson, “is to start with glatiramer acetate, and if the patients do well, and probably around 60% of them will do well, then that’s the drug of choice. But for those patients who seem to respond poorly, we now have other choices.

“There are several problems with interferons that don’t occur with glatiramer acetate,” he continued. “Depending on the interferon, as many as a third of patients may develop neutralizing antibodies, in which case the drug is no longer effective. Rare patients develop liver toxicity and have to be taken off the interferon. So there are some indications for wanting to take patients off interferon. But if they’re doing well, there is no reason to do that. Interferons have been tested long enough [for clinicians] to know that they are effective but not as effective as glatiramer acetate, and they have more problems and more side effects.”

Dr. Johnson pointed out that it is important to differentiate between efficacy and effectiveness when interpreting his study’s results. Efficacy is the finding from a [specific] population of patients like we define in clinical trials, and in those situations the drugs were probably more or less equal,” he said. “However, in effectiveness, which is the broad category of patients in the US population with any disease, the effectiveness may not be the same as efficacy, and that’s why these findings are coming out the way they are.”

ATLANTA—A pair of studies directly comparing the effectiveness of interferon beta and glatiramer acetate for patients with multiple sclerosis (MS) have found contrasting results, which are dependent on the clinical criteria that are being measured.

In one study, interferon beta-1b was more effective than glatiramer acetate in limiting the conversion of newly enhancing lesions and acute black holes to chronic black holes, which are thought to represent irreversible damage in MS, reported Stuart D. Cook, MD, and colleagues in the August 16 online Journal of Neurology, Neurosurgery, and Psychiatry. However, the two-year risk of relapse was significantly lower in patients with MS who used glatiramer acetate than among those who used interferon beta-lb, interferon beta-1a IM, and interferon beta-1a SC, reported Kenneth P. Johnson, MD, and colleagues at the 2009 Joint Meeting of the Consortium of MS Centers and Americas Committee for Treatment and Research in MS.

Chronic Black Holes in MS
Dr. Cook’s group followed 75 patients with relapsing-remitting MS or a clinically isolated syndrome in the ongoing prospective, randomized Betaseron vs Copaxone in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints (BECOME) study. The researchers used monthly 3-Tesla brain MRI scans for up to two years to observe the development and evolution of new black holes in the participants, who were randomized to receive glatiramer acetate or interferon beta-1b.

A total of 1,224 newly enhancing lesions appearing at baseline through 24 months were observed in 61 patients; 767 (62.7%) lesions showed an acute black hole. “The majority of acute black holes were transient and of similar duration by treatment group,” stated Dr. Cook, Professor of Neurosciences, University of Medicine and Dentistry of New Jersey, New Jersey Medical School in Newark, and coauthors. “Black holes are more common in patients with secondary progression than with relapsing-remitting MS and in aggressive than in benign MS.”

Follow-up scans were available for one year or more regarding 571 acute black holes. The investigators found that 103 (18.8%) black holes were still visible 12 or more months after onset and were thus characterized as chronic black holes. About 12% of the 849 newly enhancing lesions with MRI follow-up for one or more years converted to chronic black holes—9.8% with interferon beta-1b and 15.2% with glatiramer acetate. In addition, the conversion rate from acute black holes to chronic black holes was also lower with interferon beta-1b (15.2%) than with glatiramer acetate (21.4%).

“Although we did find a significantly lower conversion rate from newly enhancing lesions to chronic black holes in brain lesions that develop in patients randomized to interferon beta-1b compared to glatiramer acetate, the difference was modest,” Dr. Cook and colleagues reported. “However, this was an unexpected finding because of the widespread belief in the MS field that glatiramer acetate, but not interferon beta-1b, is neuroprotective. The analysis of the primary outcome of BECOME showed no differences by treatment group in brain MRI activity over one year or in new brain lesion formation or annualized relapse rates over two years.

“Although our study of black holes supports the view that extensive repair takes place in the majority of new brain lesions that occur in relapsing-remitting MS patients treated with first-line disease modifying therapies, it remains to be determined whether similar repair takes place in normal appearing white and gray matter and why lesion repair appears to fail over time in many patients and even early on in some patients.”

Dr. Cook noted that patients with MS are usually started on an interferon beta or glatiramer acetate, but “all are effective drugs,” he told Neurology Reviews. “There are advantages and disadvantages of each drug. Patients and physicians need to discuss the options to select the best drug based on efficacy and tolerability. All are very safe.

“As yet, there is insufficient long-term clinical data to support choosing an interferon versus glatiramer acetate. Recent studies support possible MRI benefit of interferons—for example, the REGARD, BEYOND, and BECOME studies.”

Relapse Rates in MS
Dr. Johnson’s group identified 51,162 patients with MS from an administrative claims database. The investigators conducted a series of pair-wise comparisons between patients who used glatiramer acetate and those who used each of the three interferon beta drugs under usual care conditions in the trial, which was not randomized or prospective. Demographic profiles of participants among the four treatment groups were similar, and no differences regarding use of immunomodulators was observed among patients from various geographic regions. Relapse was defined as either 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.

The researchers found that the two-year risk of relapse for patients who had received glatiramer acetate was 5.3%, compared with a rate of 13.5% in those who had received interferon beta-1b. The two-year risk of relapse for those who had taken glatiramer acetate was 5.2%, versus a rate of 10% among those who used interferon beta-1a IM. The two-year risk of relapse was 5.9% in those who had used glatiramer acetate, compared with 10.9% in those who had taken interferon beta-1a SC.

“In this recent comparison of immunomodulators for MS, the two-year risk of relapse was significantly lower for glatiramer acetate than for any of the three interferon beta drugs,” stated Dr. Johnson, Professor Emeritus of Neurology, University of Maryland, and Program Director of the Maryland Center for MS in Baltimore. “Nationwide outcomes came from treating physicians’ personal treatment decisions, free of drug company–sponsored studies or programs.”

In an interview with Neurology Reviews, Dr. Johnson said, “[Our] data show that in the broad population of patients across the US, glatiramer acetate works better than any of the interferons and is less costly, but it doesn’t work in every patient. We’re just now beginning to figure out which patients respond to which drugs.

“My recommendation,” advised Dr. Johnson, “is to start with glatiramer acetate, and if the patients do well, and probably around 60% of them will do well, then that’s the drug of choice. But for those patients who seem to respond poorly, we now have other choices.

“There are several problems with interferons that don’t occur with glatiramer acetate,” he continued. “Depending on the interferon, as many as a third of patients may develop neutralizing antibodies, in which case the drug is no longer effective. Rare patients develop liver toxicity and have to be taken off the interferon. So there are some indications for wanting to take patients off interferon. But if they’re doing well, there is no reason to do that. Interferons have been tested long enough [for clinicians] to know that they are effective but not as effective as glatiramer acetate, and they have more problems and more side effects.”

Dr. Johnson pointed out that it is important to differentiate between efficacy and effectiveness when interpreting his study’s results. Efficacy is the finding from a [specific] population of patients like we define in clinical trials, and in those situations the drugs were probably more or less equal,” he said. “However, in effectiveness, which is the broad category of patients in the US population with any disease, the effectiveness may not be the same as efficacy, and that’s why these findings are coming out the way they are.”

ATLANTA—A pair of studies directly comparing the effectiveness of interferon beta and glatiramer acetate for patients with multiple sclerosis (MS) have found contrasting results, which are dependent on the clinical criteria that are being measured.

In one study, interferon beta-1b was more effective than glatiramer acetate in limiting the conversion of newly enhancing lesions and acute black holes to chronic black holes, which are thought to represent irreversible damage in MS, reported Stuart D. Cook, MD, and colleagues in the August 16 online Journal of Neurology, Neurosurgery, and Psychiatry. However, the two-year risk of relapse was significantly lower in patients with MS who used glatiramer acetate than among those who used interferon beta-lb, interferon beta-1a IM, and interferon beta-1a SC, reported Kenneth P. Johnson, MD, and colleagues at the 2009 Joint Meeting of the Consortium of MS Centers and Americas Committee for Treatment and Research in MS.

Chronic Black Holes in MS
Dr. Cook’s group followed 75 patients with relapsing-remitting MS or a clinically isolated syndrome in the ongoing prospective, randomized Betaseron vs Copaxone in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints (BECOME) study. The researchers used monthly 3-Tesla brain MRI scans for up to two years to observe the development and evolution of new black holes in the participants, who were randomized to receive glatiramer acetate or interferon beta-1b.

A total of 1,224 newly enhancing lesions appearing at baseline through 24 months were observed in 61 patients; 767 (62.7%) lesions showed an acute black hole. “The majority of acute black holes were transient and of similar duration by treatment group,” stated Dr. Cook, Professor of Neurosciences, University of Medicine and Dentistry of New Jersey, New Jersey Medical School in Newark, and coauthors. “Black holes are more common in patients with secondary progression than with relapsing-remitting MS and in aggressive than in benign MS.”

Follow-up scans were available for one year or more regarding 571 acute black holes. The investigators found that 103 (18.8%) black holes were still visible 12 or more months after onset and were thus characterized as chronic black holes. About 12% of the 849 newly enhancing lesions with MRI follow-up for one or more years converted to chronic black holes—9.8% with interferon beta-1b and 15.2% with glatiramer acetate. In addition, the conversion rate from acute black holes to chronic black holes was also lower with interferon beta-1b (15.2%) than with glatiramer acetate (21.4%).

“Although we did find a significantly lower conversion rate from newly enhancing lesions to chronic black holes in brain lesions that develop in patients randomized to interferon beta-1b compared to glatiramer acetate, the difference was modest,” Dr. Cook and colleagues reported. “However, this was an unexpected finding because of the widespread belief in the MS field that glatiramer acetate, but not interferon beta-1b, is neuroprotective. The analysis of the primary outcome of BECOME showed no differences by treatment group in brain MRI activity over one year or in new brain lesion formation or annualized relapse rates over two years.

“Although our study of black holes supports the view that extensive repair takes place in the majority of new brain lesions that occur in relapsing-remitting MS patients treated with first-line disease modifying therapies, it remains to be determined whether similar repair takes place in normal appearing white and gray matter and why lesion repair appears to fail over time in many patients and even early on in some patients.”

Dr. Cook noted that patients with MS are usually started on an interferon beta or glatiramer acetate, but “all are effective drugs,” he told Neurology Reviews. “There are advantages and disadvantages of each drug. Patients and physicians need to discuss the options to select the best drug based on efficacy and tolerability. All are very safe.

“As yet, there is insufficient long-term clinical data to support choosing an interferon versus glatiramer acetate. Recent studies support possible MRI benefit of interferons—for example, the REGARD, BEYOND, and BECOME studies.”

Relapse Rates in MS
Dr. Johnson’s group identified 51,162 patients with MS from an administrative claims database. The investigators conducted a series of pair-wise comparisons between patients who used glatiramer acetate and those who used each of the three interferon beta drugs under usual care conditions in the trial, which was not randomized or prospective. Demographic profiles of participants among the four treatment groups were similar, and no differences regarding use of immunomodulators was observed among patients from various geographic regions. Relapse was defined as either 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.

The researchers found that the two-year risk of relapse for patients who had received glatiramer acetate was 5.3%, compared with a rate of 13.5% in those who had received interferon beta-1b. The two-year risk of relapse for those who had taken glatiramer acetate was 5.2%, versus a rate of 10% among those who used interferon beta-1a IM. The two-year risk of relapse was 5.9% in those who had used glatiramer acetate, compared with 10.9% in those who had taken interferon beta-1a SC.

“In this recent comparison of immunomodulators for MS, the two-year risk of relapse was significantly lower for glatiramer acetate than for any of the three interferon beta drugs,” stated Dr. Johnson, Professor Emeritus of Neurology, University of Maryland, and Program Director of the Maryland Center for MS in Baltimore. “Nationwide outcomes came from treating physicians’ personal treatment decisions, free of drug company–sponsored studies or programs.”

In an interview with Neurology Reviews, Dr. Johnson said, “[Our] data show that in the broad population of patients across the US, glatiramer acetate works better than any of the interferons and is less costly, but it doesn’t work in every patient. We’re just now beginning to figure out which patients respond to which drugs.

“My recommendation,” advised Dr. Johnson, “is to start with glatiramer acetate, and if the patients do well, and probably around 60% of them will do well, then that’s the drug of choice. But for those patients who seem to respond poorly, we now have other choices.

“There are several problems with interferons that don’t occur with glatiramer acetate,” he continued. “Depending on the interferon, as many as a third of patients may develop neutralizing antibodies, in which case the drug is no longer effective. Rare patients develop liver toxicity and have to be taken off the interferon. So there are some indications for wanting to take patients off interferon. But if they’re doing well, there is no reason to do that. Interferons have been tested long enough [for clinicians] to know that they are effective but not as effective as glatiramer acetate, and they have more problems and more side effects.”

Dr. Johnson pointed out that it is important to differentiate between efficacy and effectiveness when interpreting his study’s results. Efficacy is the finding from a [specific] population of patients like we define in clinical trials, and in those situations the drugs were probably more or less equal,” he said. “However, in effectiveness, which is the broad category of patients in the US population with any disease, the effectiveness may not be the same as efficacy, and that’s why these findings are coming out the way they are.”

Epstein-Barr virus, exposure to cigarette smoke, and vitamin D deficiency in children may increase the risk for adult-onset MS. A leading researcher reviews the data for these potential causes.

ATLANTA—Environmental risk factors—such as Epstein Barr virus (EBV) infection, exposure to cigarette smoke, and vitamin D deficiency—may contribute to the development of multiple sclerosis (MS) in children, reported Kassandra L. Munger, ScD, at the 2009 Joint Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

One challenge to studying risk factors for MS in children is that childhood-onset MS is rare, according to Dr. Munger, a doctoral candidate and Research Associate in the Department of Nutrition at Harvard School of Public Health in Boston. About 2% to 10% of all patients with MS are diagnosed before age 18. Therefore, studies have small sample sizes, with low statistical power, and tend to be a case-control design, which has many limitations, such as recall bias, selection bias, and reverse causation.

Studies in adults have shown a strong link between environmental risk factors and development of MS. Most epidemiologic evidence points toward EBV infection, exposure to cigarette smoke, and vitamin D deficiency as risk factors. EBV infection and cigarette smoking have been studied as risk factors for pediatric MS, noted Dr. Munger.

EBV Infection
Most people become infected with EBV during childhood; however, some individuals contract the virus during adolescence or early adulthood and are more likely to have symptomatic infection that will manifest as infectious mononucleosis. Similarities between the epidemiology of infectious mononucleosis and MS “have prompted investigators to examine whether a history of infectious mononucleosis is associated with MS risk,” Dr. Munger commented.

A meta-analysis published in 2006 found that infectious mononucleosis was associated with a more than twofold increased risk of MS. Since then, three other studies have been published—one in Denmark, one in the Netherlands, and one in Canada. “All three studies also found a greater than twofold increased risk associated with having had infectious mononucleosis,” Dr. Munger noted.

Several other studies have looked at anti-EBV antibodies and risk of MS. These studies have demonstrated a two- to ninefold increased risk of MS with elevated IgG antibodies against Epstein Barr nuclear antigens detected up to 16 to 20 years prior to MS onset.

In a meta-analysis investigating seropositivity for EBV in MS cases, 0.5% of cases were EBV-negative, compared with 6% of controls. “So being EBV-negative is associated with a 94% reduced risk of MS,” said Dr. Munger.

The association between EBV infection and risk of MS has been examined in some pediatric populations, added Dr. Munger. In a Canadian study involving 30 MS cases (mean age of onset, 12) and 90 matched controls, blood samples were collected within 1.5 years after onset of MS. Researchers found that 83% of MS cases had a history of past EBV infection, compared with 42% of controls. “So there was a greater than eightfold increased risk of MS associated with having past EBV infection,” she noted.

In a study conducted in Germany including 147 MS cases (mean age of onset, 12) and 147 matched controls, blood samples were collected an average of one year after onset of MS. More than 80% of children with MS had a history of past EBV infection, compared with 56% of controls. In addition, children with MS had higher antibody titers to viral capsid antigen and Epstein Barr nuclear antigen.

Furthermore, in a study of 96 MS cases and 96 controls from centers in North and South America, Banwell et al demonstrated that more than 80% of cases had evidence of past EBV infection, compared with 60% of controls.

“These studies strengthen the evidence that EBV may have a causal role in MS; however, confirmation in larger studies in additional populations is needed,” stated Dr. Munger.

Exposure to Cigarette Smoke
Cigarette smoking has also been implicated in the development of MS, and findings provide strong motivation for not smoking among individuals at high risk for MS, said Dr. Munger.

In a meta-analysis of prospective studies, ever smoking was associated with a 50% increased risk of MS. In addition, in the Nurses Health Study cohorts, women with one to nine pack-years of smoking had no increased risk of MS, whereas women with 10 to 24 pack-years or 25 or more pack-years of smoking had a 50% to 70% increased risk of MS.

One study of pediatric MS examined whether parental smoking was associated with risk of MS in offspring. A total of 129 confirmed cases of MS with onset before age 16 and 1,038 matched controls were included. Participants were asked if one or both parents smoked within the home before the date of MS onset or before the index date in controls. Findings demonstrated that 62% of MS cases were exposed to parental cigarette smoking, compared with 45% of matched controls. This represented a twofold increased risk of MS in children who were exposed to cigarette smoking. However, these results may be explained by recall or selection bias, she noted.

However, in another study conducted in Sweden, Montgomery et al. found that maternal smoking during pregnancy was not associated with an increased risk of MS in offspring diagnosed with MS before age 16.

Vitamin D Exposure
No studies of vitamin D exposure in pediatric MS have been published, stated Dr. Munger. However, several prospective studies in adults have looked at vitamin D by measuring sun exposure, dietary intake, and levels of serum 25-hydroxyvitamin D [25(OH)D] levels, which are an integrated measure of both sun and dietary sources. Dr. Munger noted that several case-control studies have examined vitamin D exposure in childhood and risk of developing MS as an adult. In one study conducted in Tasmania, Australia, researchers found a 50% to 60% reduced risk of MS with more than four hours of sun exposure between ages 6 and 10. In another study conducted in northern Norway, greater time spent outdoors in the summer between ages 16 and 20 was associated with a 50% reduced risk of MS. In addition, consuming fish—a primary dietary source of vitamin D—more than three times per week was associated with a 50% reduced risk of MS in this cohort. Also, in a study conducted in North America, time spent outdoors in the summer or time spent sun tanning in childhood was associated with a 60% reduced risk of MS.

Because these are case-control studies, “we have to consider that these associations could be explained by recall bias or selection bias,” said Dr. Munger. She also pointed out that another limitation of these studies is that sun exposure is not a direct measure of vitamin D exposure.

The strongest evidence to date that vitamin D may reduce MS risk comes from two prospective studies. The first, among women in the Nurses’ Health Study cohorts, found that women with a dietary intake of at least 400 IU/day of vitamin D had a 40% reduced risk of MS. The main limitation of this study, however, is that diet contributes little to the overall vitamin D nutritional status. Therefore, in the second study, vitamin D exposure was measured by blood levels of 25(OH)D in healthy young adults in the US military. Among whites, levels of 25(OH)D greater than 100 nmol/L were associated with a 50% reduced risk of MS, compared with those with levels less than 75 nmol/L. Whether adequate vitamin D nutrition is associated with a reduced risk of pediatric MS is an important question and one that is currently being studied.

Other Associations With MS Risk
“There have been some other factors in pediatric-onset MS that have been looked at,” said Dr. Munger. In a study conducted in France, researchers assessed the association between hepatitis B vaccination and pediatric-onset MS. An assessment of 143 MS cases with onset before age 16 and 1,122 matched controls showed that neither the timing nor the number of hepatitis B vaccinations was associated with MS risk. However, in a follow-up study, one specific brand of hepatitis B vaccine was associated with a threefold increased risk for MS three years after the last vaccine dose.

In the same population, researchers found that chicken pox appeared to be protective against MS, with 77% of MS cases reporting a history of clinically observed chicken pox, compared with 85% of controls.

Current evidence supports a link between EBV infection and pediatric-onset MS. Studies examining exposure to cigarette smoke and pediatric MS risk are conflicting and more studies are warranted. While there is growing evidence that vitamin D may decrease MS risk among adults, there are currently no studies in pediatric MS. A history of clinically observed chicken pox appears to be protective, and the association between hepatitis B vaccination and pediatric-onset MS remains unclear. However, confirmation of all these findings is needed in larger studies, concluded Dr. Munger.

Epstein-Barr virus, exposure to cigarette smoke, and vitamin D deficiency in children may increase the risk for adult-onset MS. A leading researcher reviews the data for these potential causes.

ATLANTA—Environmental risk factors—such as Epstein Barr virus (EBV) infection, exposure to cigarette smoke, and vitamin D deficiency—may contribute to the development of multiple sclerosis (MS) in children, reported Kassandra L. Munger, ScD, at the 2009 Joint Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

One challenge to studying risk factors for MS in children is that childhood-onset MS is rare, according to Dr. Munger, a doctoral candidate and Research Associate in the Department of Nutrition at Harvard School of Public Health in Boston. About 2% to 10% of all patients with MS are diagnosed before age 18. Therefore, studies have small sample sizes, with low statistical power, and tend to be a case-control design, which has many limitations, such as recall bias, selection bias, and reverse causation.

Studies in adults have shown a strong link between environmental risk factors and development of MS. Most epidemiologic evidence points toward EBV infection, exposure to cigarette smoke, and vitamin D deficiency as risk factors. EBV infection and cigarette smoking have been studied as risk factors for pediatric MS, noted Dr. Munger.

EBV Infection
Most people become infected with EBV during childhood; however, some individuals contract the virus during adolescence or early adulthood and are more likely to have symptomatic infection that will manifest as infectious mononucleosis. Similarities between the epidemiology of infectious mononucleosis and MS “have prompted investigators to examine whether a history of infectious mononucleosis is associated with MS risk,” Dr. Munger commented.

A meta-analysis published in 2006 found that infectious mononucleosis was associated with a more than twofold increased risk of MS. Since then, three other studies have been published—one in Denmark, one in the Netherlands, and one in Canada. “All three studies also found a greater than twofold increased risk associated with having had infectious mononucleosis,” Dr. Munger noted.

Several other studies have looked at anti-EBV antibodies and risk of MS. These studies have demonstrated a two- to ninefold increased risk of MS with elevated IgG antibodies against Epstein Barr nuclear antigens detected up to 16 to 20 years prior to MS onset.

In a meta-analysis investigating seropositivity for EBV in MS cases, 0.5% of cases were EBV-negative, compared with 6% of controls. “So being EBV-negative is associated with a 94% reduced risk of MS,” said Dr. Munger.

The association between EBV infection and risk of MS has been examined in some pediatric populations, added Dr. Munger. In a Canadian study involving 30 MS cases (mean age of onset, 12) and 90 matched controls, blood samples were collected within 1.5 years after onset of MS. Researchers found that 83% of MS cases had a history of past EBV infection, compared with 42% of controls. “So there was a greater than eightfold increased risk of MS associated with having past EBV infection,” she noted.

In a study conducted in Germany including 147 MS cases (mean age of onset, 12) and 147 matched controls, blood samples were collected an average of one year after onset of MS. More than 80% of children with MS had a history of past EBV infection, compared with 56% of controls. In addition, children with MS had higher antibody titers to viral capsid antigen and Epstein Barr nuclear antigen.

Furthermore, in a study of 96 MS cases and 96 controls from centers in North and South America, Banwell et al demonstrated that more than 80% of cases had evidence of past EBV infection, compared with 60% of controls.

“These studies strengthen the evidence that EBV may have a causal role in MS; however, confirmation in larger studies in additional populations is needed,” stated Dr. Munger.

Exposure to Cigarette Smoke
Cigarette smoking has also been implicated in the development of MS, and findings provide strong motivation for not smoking among individuals at high risk for MS, said Dr. Munger.

In a meta-analysis of prospective studies, ever smoking was associated with a 50% increased risk of MS. In addition, in the Nurses Health Study cohorts, women with one to nine pack-years of smoking had no increased risk of MS, whereas women with 10 to 24 pack-years or 25 or more pack-years of smoking had a 50% to 70% increased risk of MS.

One study of pediatric MS examined whether parental smoking was associated with risk of MS in offspring. A total of 129 confirmed cases of MS with onset before age 16 and 1,038 matched controls were included. Participants were asked if one or both parents smoked within the home before the date of MS onset or before the index date in controls. Findings demonstrated that 62% of MS cases were exposed to parental cigarette smoking, compared with 45% of matched controls. This represented a twofold increased risk of MS in children who were exposed to cigarette smoking. However, these results may be explained by recall or selection bias, she noted.

However, in another study conducted in Sweden, Montgomery et al. found that maternal smoking during pregnancy was not associated with an increased risk of MS in offspring diagnosed with MS before age 16.

Vitamin D Exposure
No studies of vitamin D exposure in pediatric MS have been published, stated Dr. Munger. However, several prospective studies in adults have looked at vitamin D by measuring sun exposure, dietary intake, and levels of serum 25-hydroxyvitamin D [25(OH)D] levels, which are an integrated measure of both sun and dietary sources. Dr. Munger noted that several case-control studies have examined vitamin D exposure in childhood and risk of developing MS as an adult. In one study conducted in Tasmania, Australia, researchers found a 50% to 60% reduced risk of MS with more than four hours of sun exposure between ages 6 and 10. In another study conducted in northern Norway, greater time spent outdoors in the summer between ages 16 and 20 was associated with a 50% reduced risk of MS. In addition, consuming fish—a primary dietary source of vitamin D—more than three times per week was associated with a 50% reduced risk of MS in this cohort. Also, in a study conducted in North America, time spent outdoors in the summer or time spent sun tanning in childhood was associated with a 60% reduced risk of MS.

Because these are case-control studies, “we have to consider that these associations could be explained by recall bias or selection bias,” said Dr. Munger. She also pointed out that another limitation of these studies is that sun exposure is not a direct measure of vitamin D exposure.

The strongest evidence to date that vitamin D may reduce MS risk comes from two prospective studies. The first, among women in the Nurses’ Health Study cohorts, found that women with a dietary intake of at least 400 IU/day of vitamin D had a 40% reduced risk of MS. The main limitation of this study, however, is that diet contributes little to the overall vitamin D nutritional status. Therefore, in the second study, vitamin D exposure was measured by blood levels of 25(OH)D in healthy young adults in the US military. Among whites, levels of 25(OH)D greater than 100 nmol/L were associated with a 50% reduced risk of MS, compared with those with levels less than 75 nmol/L. Whether adequate vitamin D nutrition is associated with a reduced risk of pediatric MS is an important question and one that is currently being studied.

Other Associations With MS Risk
“There have been some other factors in pediatric-onset MS that have been looked at,” said Dr. Munger. In a study conducted in France, researchers assessed the association between hepatitis B vaccination and pediatric-onset MS. An assessment of 143 MS cases with onset before age 16 and 1,122 matched controls showed that neither the timing nor the number of hepatitis B vaccinations was associated with MS risk. However, in a follow-up study, one specific brand of hepatitis B vaccine was associated with a threefold increased risk for MS three years after the last vaccine dose.

In the same population, researchers found that chicken pox appeared to be protective against MS, with 77% of MS cases reporting a history of clinically observed chicken pox, compared with 85% of controls.

Current evidence supports a link between EBV infection and pediatric-onset MS. Studies examining exposure to cigarette smoke and pediatric MS risk are conflicting and more studies are warranted. While there is growing evidence that vitamin D may decrease MS risk among adults, there are currently no studies in pediatric MS. A history of clinically observed chicken pox appears to be protective, and the association between hepatitis B vaccination and pediatric-onset MS remains unclear. However, confirmation of all these findings is needed in larger studies, concluded Dr. Munger.

Epstein-Barr virus, exposure to cigarette smoke, and vitamin D deficiency in children may increase the risk for adult-onset MS. A leading researcher reviews the data for these potential causes.

ATLANTA—Environmental risk factors—such as Epstein Barr virus (EBV) infection, exposure to cigarette smoke, and vitamin D deficiency—may contribute to the development of multiple sclerosis (MS) in children, reported Kassandra L. Munger, ScD, at the 2009 Joint Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

One challenge to studying risk factors for MS in children is that childhood-onset MS is rare, according to Dr. Munger, a doctoral candidate and Research Associate in the Department of Nutrition at Harvard School of Public Health in Boston. About 2% to 10% of all patients with MS are diagnosed before age 18. Therefore, studies have small sample sizes, with low statistical power, and tend to be a case-control design, which has many limitations, such as recall bias, selection bias, and reverse causation.

Studies in adults have shown a strong link between environmental risk factors and development of MS. Most epidemiologic evidence points toward EBV infection, exposure to cigarette smoke, and vitamin D deficiency as risk factors. EBV infection and cigarette smoking have been studied as risk factors for pediatric MS, noted Dr. Munger.

EBV Infection
Most people become infected with EBV during childhood; however, some individuals contract the virus during adolescence or early adulthood and are more likely to have symptomatic infection that will manifest as infectious mononucleosis. Similarities between the epidemiology of infectious mononucleosis and MS “have prompted investigators to examine whether a history of infectious mononucleosis is associated with MS risk,” Dr. Munger commented.

A meta-analysis published in 2006 found that infectious mononucleosis was associated with a more than twofold increased risk of MS. Since then, three other studies have been published—one in Denmark, one in the Netherlands, and one in Canada. “All three studies also found a greater than twofold increased risk associated with having had infectious mononucleosis,” Dr. Munger noted.

Several other studies have looked at anti-EBV antibodies and risk of MS. These studies have demonstrated a two- to ninefold increased risk of MS with elevated IgG antibodies against Epstein Barr nuclear antigens detected up to 16 to 20 years prior to MS onset.

In a meta-analysis investigating seropositivity for EBV in MS cases, 0.5% of cases were EBV-negative, compared with 6% of controls. “So being EBV-negative is associated with a 94% reduced risk of MS,” said Dr. Munger.

The association between EBV infection and risk of MS has been examined in some pediatric populations, added Dr. Munger. In a Canadian study involving 30 MS cases (mean age of onset, 12) and 90 matched controls, blood samples were collected within 1.5 years after onset of MS. Researchers found that 83% of MS cases had a history of past EBV infection, compared with 42% of controls. “So there was a greater than eightfold increased risk of MS associated with having past EBV infection,” she noted.

In a study conducted in Germany including 147 MS cases (mean age of onset, 12) and 147 matched controls, blood samples were collected an average of one year after onset of MS. More than 80% of children with MS had a history of past EBV infection, compared with 56% of controls. In addition, children with MS had higher antibody titers to viral capsid antigen and Epstein Barr nuclear antigen.

Furthermore, in a study of 96 MS cases and 96 controls from centers in North and South America, Banwell et al demonstrated that more than 80% of cases had evidence of past EBV infection, compared with 60% of controls.

“These studies strengthen the evidence that EBV may have a causal role in MS; however, confirmation in larger studies in additional populations is needed,” stated Dr. Munger.

Exposure to Cigarette Smoke
Cigarette smoking has also been implicated in the development of MS, and findings provide strong motivation for not smoking among individuals at high risk for MS, said Dr. Munger.

In a meta-analysis of prospective studies, ever smoking was associated with a 50% increased risk of MS. In addition, in the Nurses Health Study cohorts, women with one to nine pack-years of smoking had no increased risk of MS, whereas women with 10 to 24 pack-years or 25 or more pack-years of smoking had a 50% to 70% increased risk of MS.

One study of pediatric MS examined whether parental smoking was associated with risk of MS in offspring. A total of 129 confirmed cases of MS with onset before age 16 and 1,038 matched controls were included. Participants were asked if one or both parents smoked within the home before the date of MS onset or before the index date in controls. Findings demonstrated that 62% of MS cases were exposed to parental cigarette smoking, compared with 45% of matched controls. This represented a twofold increased risk of MS in children who were exposed to cigarette smoking. However, these results may be explained by recall or selection bias, she noted.

However, in another study conducted in Sweden, Montgomery et al. found that maternal smoking during pregnancy was not associated with an increased risk of MS in offspring diagnosed with MS before age 16.

Vitamin D Exposure
No studies of vitamin D exposure in pediatric MS have been published, stated Dr. Munger. However, several prospective studies in adults have looked at vitamin D by measuring sun exposure, dietary intake, and levels of serum 25-hydroxyvitamin D [25(OH)D] levels, which are an integrated measure of both sun and dietary sources. Dr. Munger noted that several case-control studies have examined vitamin D exposure in childhood and risk of developing MS as an adult. In one study conducted in Tasmania, Australia, researchers found a 50% to 60% reduced risk of MS with more than four hours of sun exposure between ages 6 and 10. In another study conducted in northern Norway, greater time spent outdoors in the summer between ages 16 and 20 was associated with a 50% reduced risk of MS. In addition, consuming fish—a primary dietary source of vitamin D—more than three times per week was associated with a 50% reduced risk of MS in this cohort. Also, in a study conducted in North America, time spent outdoors in the summer or time spent sun tanning in childhood was associated with a 60% reduced risk of MS.

Because these are case-control studies, “we have to consider that these associations could be explained by recall bias or selection bias,” said Dr. Munger. She also pointed out that another limitation of these studies is that sun exposure is not a direct measure of vitamin D exposure.

The strongest evidence to date that vitamin D may reduce MS risk comes from two prospective studies. The first, among women in the Nurses’ Health Study cohorts, found that women with a dietary intake of at least 400 IU/day of vitamin D had a 40% reduced risk of MS. The main limitation of this study, however, is that diet contributes little to the overall vitamin D nutritional status. Therefore, in the second study, vitamin D exposure was measured by blood levels of 25(OH)D in healthy young adults in the US military. Among whites, levels of 25(OH)D greater than 100 nmol/L were associated with a 50% reduced risk of MS, compared with those with levels less than 75 nmol/L. Whether adequate vitamin D nutrition is associated with a reduced risk of pediatric MS is an important question and one that is currently being studied.

Other Associations With MS Risk
“There have been some other factors in pediatric-onset MS that have been looked at,” said Dr. Munger. In a study conducted in France, researchers assessed the association between hepatitis B vaccination and pediatric-onset MS. An assessment of 143 MS cases with onset before age 16 and 1,122 matched controls showed that neither the timing nor the number of hepatitis B vaccinations was associated with MS risk. However, in a follow-up study, one specific brand of hepatitis B vaccine was associated with a threefold increased risk for MS three years after the last vaccine dose.

In the same population, researchers found that chicken pox appeared to be protective against MS, with 77% of MS cases reporting a history of clinically observed chicken pox, compared with 85% of controls.

Current evidence supports a link between EBV infection and pediatric-onset MS. Studies examining exposure to cigarette smoke and pediatric MS risk are conflicting and more studies are warranted. While there is growing evidence that vitamin D may decrease MS risk among adults, there are currently no studies in pediatric MS. A history of clinically observed chicken pox appears to be protective, and the association between hepatitis B vaccination and pediatric-onset MS remains unclear. However, confirmation of all these findings is needed in larger studies, concluded Dr. Munger.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

If Effective, What Is an Appropriate Dose?

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

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

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

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

Safety and Efficacy of High-Dose Vitamin D

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

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

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

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

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

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

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

Vitamin D Deficiency Linked to MS Severity

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

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

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

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

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

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

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

—Colby Stong

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

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

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

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

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

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

If Effective, What Is an Appropriate Dose?

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

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

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

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

Safety and Efficacy of High-Dose Vitamin D

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

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

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

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

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

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

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

Vitamin D Deficiency Linked to MS Severity

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

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

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

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

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

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

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

—Colby Stong

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

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

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

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

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

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

If Effective, What Is an Appropriate Dose?

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

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

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

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

Safety and Efficacy of High-Dose Vitamin D

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

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

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

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

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

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

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

Vitamin D Deficiency Linked to MS Severity

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

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

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

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

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

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

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

—Colby Stong

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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