Multiple Sclerosis

The epidemic of immune diseases that swept through the developed world during the 20th century may have resulted from a disruption in the delicate balance achieved throughout evolution between humans and certain parasitic fellow travelers, according to Dr. Joel V. Weinstock.

Diseases such as inflammatory bowel disease (IBD) were rare before the 1920s, when public health efforts began making significant strides in cleaning up the water supply, modernizing sewage treatment, and improving farming practices. While these efforts clearly had major benefits in curtailing or eliminating exposure to many disease-causing pathogens, they also had the unintended consequence of removing exposure to beneficial or even necessary organisms.

“People today live very differently than they did throughout history. People used to live close to the soil, without indoor plumbing, often with direct exposure to animals,” said Dr. Weinstock, professor of medicine, Tufts Medical Center and Tufts University Sackler School of Graduate Biomedical Sciences, Boston.

The result was near universal colonization with helminths, which are complex wormlike animals that inhabit the gastrointestinal tract of mammals. Like the myriad bacteria also found in the gut performing important tasks such as producing vitamins and aiding in digestion, some helminths can cause disease in the host but many are relatively harmless and, in fact, are important regulators of our immune systems.

“We have known for many years that helminths exert a powerful effect on immunity in the host, primarily by inducing the regulatory arm of the immune system, which is important in reigning in the effector 'fight and kill' arm of the immune system,” he said. The regulatory arm hones and shapes the immune response to bacteria, viruses, and parasites, quelling the effects of the effector arm so as to prevent needless tissue damage.

At least one rheumatologist was skeptical. “This is an interesting theory—but just that. We need more documentation,” said Dr. Roy D. Altman, professor of medicine, rheumatology, and immunology at the University of California, Los Angeles, in an interview.

“In addition, longevity increases with the elimination of parasites. It may be that people are living longer and this allows them to get immune diseases like rheumatoid arthritis.”

When other researchers were investigating possible environmental causes for the increase in these diseases, such as exposure to food dyes or from vaccinations, Dr. Weinstock took a different approach, looking for something in the environment that had been protective and had been lost. “It occurred to us that the deworming of the population—a major public health project early in the 20th century—took place at the same time as the incidence of immunologic diseases really took off,” he said.

Moreover, diseases such as asthma, IBD, rheumatoid arthritis, and multiple sclerosis remain uncommon in less-developed parts of the world where helminthic colonization is still widespread.

Because Dr. Weinstock is a gastroenterologist with a special interest in immunology, his subsequent investigations in animals and humans have focused on IBD.

Initial animal experiments determined that helminth exposure could both prevent and reverse induced colitis in mice by inhibiting inflammatory cytokines such as tumor necrosis factor-β and interleukin (IL)-12 or by promoting the production of regulatory cytokines such as IL-10 and transforming growth factor-β (Int. J. Parasitol. 2007;37:457–64).

In a pilot study of 29 adult patients with longstanding, refractory Crohn's disease, patients were given a drink containing 2,500 specially prepared ova of Trichuris suis, the pig whipworm, every 3 weeks for 24 weeks. Ingestion of this helminth, which is similar to the human whipworm, causes a short-term colonization in the human gastrointestinal tract.

By the 12th week, 22 patients (76%) had responded to the treatment, with a decrease in the Crohn's disease activity index (CDAI) of more than 100 points or below 150, and 19 patients (66%) were in remission, with a CDAI below 150.

At the 24th week, 23 patients (79%) were responders and 21 (72%) were in remission (Gut 2005;54:87–90).

In a subsequent double-blind trial that enrolled 54 adult patients with ulcerative colitis, participants received 2,500 T. suis ova in a liquid drink or a placebo drink every 2 weeks for 12 weeks.

Favorable responses, with decreases in the ulcerative colitis disease activity index of 4 or more points on an index ranging from 0 to 12, were seen in 13 patients receiving the active treatment (43%) compared with 4 receiving placebo (17%).

Similar findings have been shown in several other autoimmune conditions. Prospective data have shown that children with helminths are less likely to develop allergies, and disease has been arrested in patients with multiple sclerosis following helminth colonization. Researchers in the United Kingdom have been investigating modulation of the immune system in rheumatoid arthritis. They tested an anti-inflammatory phosphorylcholine-containing glycoprotein secreted by the nematode Acanthocheilonema viteae in collagen-induced arthritic mice, finding a reduction in the severity of arthritis and suppression of collagen-specific T-1 cytokine production (Ann. Rheum. Dis. 2008;67:518–23).

Dr. Weinstock believes that helminths and human hosts evolved to the benefit of both over millennia. Petrified human stool many thousands of years old has been found to contain helminth eggs, and autopsies of mummies have found traces of helminths. The frozen iceman Ötzi, found in the northern Italian Alps in 1991 where he had lain buried in a glacier since 3300 B.C., had T. trichiura in his gut.

“We are teeming with life, and we really are part of the environment. When we try to separate ourselves from the environment and exposures to these organisms, we leave ourselves predisposed to disease,” he said.

Dr. Weinstock is not advocating a return to 19th-century hygiene. Rather, he and others are working to characterize more fully the interaction of helminths with the immune system and to identify factors responsible for the beneficial exposures so they can be reintroduced at an appropriate time early in life, when the immune system is developing.

Clinical studies in IBD, asthma, rhinoconjunctivitis, and multiple sclerosis are underway and more are planned, and one helminth-derived medication, ASP1002, is under review by the Food and Drug Administration and the European drug monitoring authorities.

Dr. Francois-Xavier Frapaise, CEO of Asphelia Pharmaceuticals Inc., confirmed that his company is about to file an Investigational New Drug application for ASP1002 in Crohn's disease. They also are planning trials in various other conditions including lupus and multiple sclerosis. “RA would also be interesting to investigate,” he said.

“There has been a revolution in our thinking,” Dr. Weinstock said. “We have learned that we are not insulated from the world around us.”

Helminths, like this whipworm, could be the next big thing in multiple sclerosis and other autoimmune diseases. Courtesy Dr. Joel V. Weinstock

The epidemic of immune diseases that swept through the developed world during the 20th century may have resulted from a disruption in the delicate balance achieved throughout evolution between humans and certain parasitic fellow travelers, according to Dr. Joel V. Weinstock.

Diseases such as inflammatory bowel disease (IBD) were rare before the 1920s, when public health efforts began making significant strides in cleaning up the water supply, modernizing sewage treatment, and improving farming practices. While these efforts clearly had major benefits in curtailing or eliminating exposure to many disease-causing pathogens, they also had the unintended consequence of removing exposure to beneficial or even necessary organisms.

“People today live very differently than they did throughout history. People used to live close to the soil, without indoor plumbing, often with direct exposure to animals,” said Dr. Weinstock, professor of medicine, Tufts Medical Center and Tufts University Sackler School of Graduate Biomedical Sciences, Boston.

The result was near universal colonization with helminths, which are complex wormlike animals that inhabit the gastrointestinal tract of mammals. Like the myriad bacteria also found in the gut performing important tasks such as producing vitamins and aiding in digestion, some helminths can cause disease in the host but many are relatively harmless and, in fact, are important regulators of our immune systems.

“We have known for many years that helminths exert a powerful effect on immunity in the host, primarily by inducing the regulatory arm of the immune system, which is important in reigning in the effector 'fight and kill' arm of the immune system,” he said. The regulatory arm hones and shapes the immune response to bacteria, viruses, and parasites, quelling the effects of the effector arm so as to prevent needless tissue damage.

At least one rheumatologist was skeptical. “This is an interesting theory—but just that. We need more documentation,” said Dr. Roy D. Altman, professor of medicine, rheumatology, and immunology at the University of California, Los Angeles, in an interview.

“In addition, longevity increases with the elimination of parasites. It may be that people are living longer and this allows them to get immune diseases like rheumatoid arthritis.”

When other researchers were investigating possible environmental causes for the increase in these diseases, such as exposure to food dyes or from vaccinations, Dr. Weinstock took a different approach, looking for something in the environment that had been protective and had been lost. “It occurred to us that the deworming of the population—a major public health project early in the 20th century—took place at the same time as the incidence of immunologic diseases really took off,” he said.

Moreover, diseases such as asthma, IBD, rheumatoid arthritis, and multiple sclerosis remain uncommon in less-developed parts of the world where helminthic colonization is still widespread.

Because Dr. Weinstock is a gastroenterologist with a special interest in immunology, his subsequent investigations in animals and humans have focused on IBD.

Initial animal experiments determined that helminth exposure could both prevent and reverse induced colitis in mice by inhibiting inflammatory cytokines such as tumor necrosis factor-β and interleukin (IL)-12 or by promoting the production of regulatory cytokines such as IL-10 and transforming growth factor-β (Int. J. Parasitol. 2007;37:457–64).

In a pilot study of 29 adult patients with longstanding, refractory Crohn's disease, patients were given a drink containing 2,500 specially prepared ova of Trichuris suis, the pig whipworm, every 3 weeks for 24 weeks. Ingestion of this helminth, which is similar to the human whipworm, causes a short-term colonization in the human gastrointestinal tract.

By the 12th week, 22 patients (76%) had responded to the treatment, with a decrease in the Crohn's disease activity index (CDAI) of more than 100 points or below 150, and 19 patients (66%) were in remission, with a CDAI below 150.

At the 24th week, 23 patients (79%) were responders and 21 (72%) were in remission (Gut 2005;54:87–90).

In a subsequent double-blind trial that enrolled 54 adult patients with ulcerative colitis, participants received 2,500 T. suis ova in a liquid drink or a placebo drink every 2 weeks for 12 weeks.

Favorable responses, with decreases in the ulcerative colitis disease activity index of 4 or more points on an index ranging from 0 to 12, were seen in 13 patients receiving the active treatment (43%) compared with 4 receiving placebo (17%).

Similar findings have been shown in several other autoimmune conditions. Prospective data have shown that children with helminths are less likely to develop allergies, and disease has been arrested in patients with multiple sclerosis following helminth colonization. Researchers in the United Kingdom have been investigating modulation of the immune system in rheumatoid arthritis. They tested an anti-inflammatory phosphorylcholine-containing glycoprotein secreted by the nematode Acanthocheilonema viteae in collagen-induced arthritic mice, finding a reduction in the severity of arthritis and suppression of collagen-specific T-1 cytokine production (Ann. Rheum. Dis. 2008;67:518–23).

Dr. Weinstock believes that helminths and human hosts evolved to the benefit of both over millennia. Petrified human stool many thousands of years old has been found to contain helminth eggs, and autopsies of mummies have found traces of helminths. The frozen iceman Ötzi, found in the northern Italian Alps in 1991 where he had lain buried in a glacier since 3300 B.C., had T. trichiura in his gut.

“We are teeming with life, and we really are part of the environment. When we try to separate ourselves from the environment and exposures to these organisms, we leave ourselves predisposed to disease,” he said.

Dr. Weinstock is not advocating a return to 19th-century hygiene. Rather, he and others are working to characterize more fully the interaction of helminths with the immune system and to identify factors responsible for the beneficial exposures so they can be reintroduced at an appropriate time early in life, when the immune system is developing.

Clinical studies in IBD, asthma, rhinoconjunctivitis, and multiple sclerosis are underway and more are planned, and one helminth-derived medication, ASP1002, is under review by the Food and Drug Administration and the European drug monitoring authorities.

Dr. Francois-Xavier Frapaise, CEO of Asphelia Pharmaceuticals Inc., confirmed that his company is about to file an Investigational New Drug application for ASP1002 in Crohn's disease. They also are planning trials in various other conditions including lupus and multiple sclerosis. “RA would also be interesting to investigate,” he said.

“There has been a revolution in our thinking,” Dr. Weinstock said. “We have learned that we are not insulated from the world around us.”

Helminths, like this whipworm, could be the next big thing in multiple sclerosis and other autoimmune diseases. Courtesy Dr. Joel V. Weinstock

The epidemic of immune diseases that swept through the developed world during the 20th century may have resulted from a disruption in the delicate balance achieved throughout evolution between humans and certain parasitic fellow travelers, according to Dr. Joel V. Weinstock.

Diseases such as inflammatory bowel disease (IBD) were rare before the 1920s, when public health efforts began making significant strides in cleaning up the water supply, modernizing sewage treatment, and improving farming practices. While these efforts clearly had major benefits in curtailing or eliminating exposure to many disease-causing pathogens, they also had the unintended consequence of removing exposure to beneficial or even necessary organisms.

“People today live very differently than they did throughout history. People used to live close to the soil, without indoor plumbing, often with direct exposure to animals,” said Dr. Weinstock, professor of medicine, Tufts Medical Center and Tufts University Sackler School of Graduate Biomedical Sciences, Boston.

The result was near universal colonization with helminths, which are complex wormlike animals that inhabit the gastrointestinal tract of mammals. Like the myriad bacteria also found in the gut performing important tasks such as producing vitamins and aiding in digestion, some helminths can cause disease in the host but many are relatively harmless and, in fact, are important regulators of our immune systems.

“We have known for many years that helminths exert a powerful effect on immunity in the host, primarily by inducing the regulatory arm of the immune system, which is important in reigning in the effector 'fight and kill' arm of the immune system,” he said. The regulatory arm hones and shapes the immune response to bacteria, viruses, and parasites, quelling the effects of the effector arm so as to prevent needless tissue damage.

At least one rheumatologist was skeptical. “This is an interesting theory—but just that. We need more documentation,” said Dr. Roy D. Altman, professor of medicine, rheumatology, and immunology at the University of California, Los Angeles, in an interview.

“In addition, longevity increases with the elimination of parasites. It may be that people are living longer and this allows them to get immune diseases like rheumatoid arthritis.”

When other researchers were investigating possible environmental causes for the increase in these diseases, such as exposure to food dyes or from vaccinations, Dr. Weinstock took a different approach, looking for something in the environment that had been protective and had been lost. “It occurred to us that the deworming of the population—a major public health project early in the 20th century—took place at the same time as the incidence of immunologic diseases really took off,” he said.

Moreover, diseases such as asthma, IBD, rheumatoid arthritis, and multiple sclerosis remain uncommon in less-developed parts of the world where helminthic colonization is still widespread.

Because Dr. Weinstock is a gastroenterologist with a special interest in immunology, his subsequent investigations in animals and humans have focused on IBD.

Initial animal experiments determined that helminth exposure could both prevent and reverse induced colitis in mice by inhibiting inflammatory cytokines such as tumor necrosis factor-β and interleukin (IL)-12 or by promoting the production of regulatory cytokines such as IL-10 and transforming growth factor-β (Int. J. Parasitol. 2007;37:457–64).

In a pilot study of 29 adult patients with longstanding, refractory Crohn's disease, patients were given a drink containing 2,500 specially prepared ova of Trichuris suis, the pig whipworm, every 3 weeks for 24 weeks. Ingestion of this helminth, which is similar to the human whipworm, causes a short-term colonization in the human gastrointestinal tract.

By the 12th week, 22 patients (76%) had responded to the treatment, with a decrease in the Crohn's disease activity index (CDAI) of more than 100 points or below 150, and 19 patients (66%) were in remission, with a CDAI below 150.

At the 24th week, 23 patients (79%) were responders and 21 (72%) were in remission (Gut 2005;54:87–90).

In a subsequent double-blind trial that enrolled 54 adult patients with ulcerative colitis, participants received 2,500 T. suis ova in a liquid drink or a placebo drink every 2 weeks for 12 weeks.

Favorable responses, with decreases in the ulcerative colitis disease activity index of 4 or more points on an index ranging from 0 to 12, were seen in 13 patients receiving the active treatment (43%) compared with 4 receiving placebo (17%).

Similar findings have been shown in several other autoimmune conditions. Prospective data have shown that children with helminths are less likely to develop allergies, and disease has been arrested in patients with multiple sclerosis following helminth colonization. Researchers in the United Kingdom have been investigating modulation of the immune system in rheumatoid arthritis. They tested an anti-inflammatory phosphorylcholine-containing glycoprotein secreted by the nematode Acanthocheilonema viteae in collagen-induced arthritic mice, finding a reduction in the severity of arthritis and suppression of collagen-specific T-1 cytokine production (Ann. Rheum. Dis. 2008;67:518–23).

Dr. Weinstock believes that helminths and human hosts evolved to the benefit of both over millennia. Petrified human stool many thousands of years old has been found to contain helminth eggs, and autopsies of mummies have found traces of helminths. The frozen iceman Ötzi, found in the northern Italian Alps in 1991 where he had lain buried in a glacier since 3300 B.C., had T. trichiura in his gut.

“We are teeming with life, and we really are part of the environment. When we try to separate ourselves from the environment and exposures to these organisms, we leave ourselves predisposed to disease,” he said.

Dr. Weinstock is not advocating a return to 19th-century hygiene. Rather, he and others are working to characterize more fully the interaction of helminths with the immune system and to identify factors responsible for the beneficial exposures so they can be reintroduced at an appropriate time early in life, when the immune system is developing.

Clinical studies in IBD, asthma, rhinoconjunctivitis, and multiple sclerosis are underway and more are planned, and one helminth-derived medication, ASP1002, is under review by the Food and Drug Administration and the European drug monitoring authorities.

Dr. Francois-Xavier Frapaise, CEO of Asphelia Pharmaceuticals Inc., confirmed that his company is about to file an Investigational New Drug application for ASP1002 in Crohn's disease. They also are planning trials in various other conditions including lupus and multiple sclerosis. “RA would also be interesting to investigate,” he said.

“There has been a revolution in our thinking,” Dr. Weinstock said. “We have learned that we are not insulated from the world around us.”

Helminths, like this whipworm, could be the next big thing in multiple sclerosis and other autoimmune diseases. Courtesy Dr. Joel V. Weinstock

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

MONTREAL—Macrophages and microglia represent rational targets in the treatment of patients with multiple sclerosis (MS), given that these cells are key effectors for tissue injury in inflammatory conditions in the CNS, said Samia J. Khoury, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis.
Therapies that inhibit microglial activation may be beneficial in chronic inflammatory diseases of the central nervous system such as MS. Potential inhibitors of microglia activation are peroxisome proliferator-activated receptor γ (PPAR-γ) agonists, anti-CD200 antibodies, and minocycline. Dr. Khoury discussed the role of reactive microglia in the initiation and propagation of immune responses as inflammatory mediators during inflammation in the CNS.

The acute MS lesion has been classically defined based on the presence of microglia ingesting myelin components and a lymphocyte inflammatory response. The chronic MS lesion, characteristic of the progressive phase of the disease, is dominated by the presence of activated microglia/macrophages without a prominent lymphocytic infiltrate. Human adult microglia can phagocytose myelin vesicles and secrete proinflammatory cytokines such as interleukin 1 (IL‑1), IL-6, and tumor necrosis factor α (TNF-α), and they are also known to undergo oxidative bursts. Diffuse injury of the normal-appearing white matter and cortical demyelination are classic hallmarks of primary and secondary progressive MS. The inflammation consists of mononuclear cells and diffuse infiltration of the tissue by T lymphocytes associated with profound activation of microglia.

Similar to patients with MS, the peak of disease activity in mice with experimental autoimmune encephalomyelitis (EAE)—a widely used animal model in MS—is characterized by T-cell infiltrates that decline during extended follow-up, whereas the microglia are activated persistently throughout the chronic phases. “This activation correlates well with the presence of cortical lesions, alteration of synaptic function, and axonal transport, each indicative of neuronal dysfunction,” said Dr. Khoury, Professor of Neurology at Brigham and Women’s Hospital in Boston. These data suggest that inflammation is sustained by microglia during the chronic phase of EAE.

The contribution of microglia to the progression of MS is evident in the following:
• Progressive MS correlates with the presence of diffuse axonal injury and activated microglia in the cortex and nonlesioned white matter.
• Increased expression of the major histocompatibility complex class II (MHC II) gene is found on microglia in nonlesioned white matter in the brains of patients with MS.
• Proinflammatory mediators released by microglia appear to be important contributors in blocking neurogenesis.
• Activation of microglia results in secretion of nitric oxide and proinflammatory cytokines such as IL-1, IL-6, IL-8, macrophage inflammatory protein 1-α, monocyte chemotactic protein 1, and TNF-α.
• Microglia in the subventricular zone proliferate and closely contact the neural stem cells.
Compounds that inhibit microglia activation include PPAR-γ agonists, anti-CD200 antibodies, and minocycline. PPAR-γ is a nuclear receptor that controls reproduction, metabolism, development, and immune responses. Natural and synthetic PPAR-γ agonists may control brain inflammation by inhibiting microglial activation, noted Dr. Khoury.

CD200 is expressed on neurons, and CD200R is expressed on macrophages/microglia. CD200-null mice experience an earlier onset of EAE, accompanied by an increased number and accumulation of activated macrophages and microglia in the CNS. After facial nerve transection, CD200-null mice have shown accelerated microglial response around neurons. Slow Wallerian degeneration mice have up-regulated CD200 and protection from EAE.

Minocycline has been shown to ameliorate EAE by peripheral immunomodulatory properties. Its mechanisms of action include inhibition of matrix metalloproteinase 2 activity and inhibition of inducible nitric oxide synthase, prostaglandin-E2, caspase-1, caspase-3, and cyclo-oxygenase–2 expressions, as well as the impairment of cytokine production. Some of these mechanisms are manifested, at least in part, by inhibition of mitogen-activated protein kinases. Minocycline also inhibits protein kinase C activation and decreases MHC II expression.

MONTREAL—Macrophages and microglia represent rational targets in the treatment of patients with multiple sclerosis (MS), given that these cells are key effectors for tissue injury in inflammatory conditions in the CNS, said Samia J. Khoury, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis.
Therapies that inhibit microglial activation may be beneficial in chronic inflammatory diseases of the central nervous system such as MS. Potential inhibitors of microglia activation are peroxisome proliferator-activated receptor γ (PPAR-γ) agonists, anti-CD200 antibodies, and minocycline. Dr. Khoury discussed the role of reactive microglia in the initiation and propagation of immune responses as inflammatory mediators during inflammation in the CNS.

The acute MS lesion has been classically defined based on the presence of microglia ingesting myelin components and a lymphocyte inflammatory response. The chronic MS lesion, characteristic of the progressive phase of the disease, is dominated by the presence of activated microglia/macrophages without a prominent lymphocytic infiltrate. Human adult microglia can phagocytose myelin vesicles and secrete proinflammatory cytokines such as interleukin 1 (IL‑1), IL-6, and tumor necrosis factor α (TNF-α), and they are also known to undergo oxidative bursts. Diffuse injury of the normal-appearing white matter and cortical demyelination are classic hallmarks of primary and secondary progressive MS. The inflammation consists of mononuclear cells and diffuse infiltration of the tissue by T lymphocytes associated with profound activation of microglia.

Similar to patients with MS, the peak of disease activity in mice with experimental autoimmune encephalomyelitis (EAE)—a widely used animal model in MS—is characterized by T-cell infiltrates that decline during extended follow-up, whereas the microglia are activated persistently throughout the chronic phases. “This activation correlates well with the presence of cortical lesions, alteration of synaptic function, and axonal transport, each indicative of neuronal dysfunction,” said Dr. Khoury, Professor of Neurology at Brigham and Women’s Hospital in Boston. These data suggest that inflammation is sustained by microglia during the chronic phase of EAE.

The contribution of microglia to the progression of MS is evident in the following:
• Progressive MS correlates with the presence of diffuse axonal injury and activated microglia in the cortex and nonlesioned white matter.
• Increased expression of the major histocompatibility complex class II (MHC II) gene is found on microglia in nonlesioned white matter in the brains of patients with MS.
• Proinflammatory mediators released by microglia appear to be important contributors in blocking neurogenesis.
• Activation of microglia results in secretion of nitric oxide and proinflammatory cytokines such as IL-1, IL-6, IL-8, macrophage inflammatory protein 1-α, monocyte chemotactic protein 1, and TNF-α.
• Microglia in the subventricular zone proliferate and closely contact the neural stem cells.
Compounds that inhibit microglia activation include PPAR-γ agonists, anti-CD200 antibodies, and minocycline. PPAR-γ is a nuclear receptor that controls reproduction, metabolism, development, and immune responses. Natural and synthetic PPAR-γ agonists may control brain inflammation by inhibiting microglial activation, noted Dr. Khoury.

CD200 is expressed on neurons, and CD200R is expressed on macrophages/microglia. CD200-null mice experience an earlier onset of EAE, accompanied by an increased number and accumulation of activated macrophages and microglia in the CNS. After facial nerve transection, CD200-null mice have shown accelerated microglial response around neurons. Slow Wallerian degeneration mice have up-regulated CD200 and protection from EAE.

Minocycline has been shown to ameliorate EAE by peripheral immunomodulatory properties. Its mechanisms of action include inhibition of matrix metalloproteinase 2 activity and inhibition of inducible nitric oxide synthase, prostaglandin-E2, caspase-1, caspase-3, and cyclo-oxygenase–2 expressions, as well as the impairment of cytokine production. Some of these mechanisms are manifested, at least in part, by inhibition of mitogen-activated protein kinases. Minocycline also inhibits protein kinase C activation and decreases MHC II expression.

MONTREAL—Macrophages and microglia represent rational targets in the treatment of patients with multiple sclerosis (MS), given that these cells are key effectors for tissue injury in inflammatory conditions in the CNS, said Samia J. Khoury, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis.
Therapies that inhibit microglial activation may be beneficial in chronic inflammatory diseases of the central nervous system such as MS. Potential inhibitors of microglia activation are peroxisome proliferator-activated receptor γ (PPAR-γ) agonists, anti-CD200 antibodies, and minocycline. Dr. Khoury discussed the role of reactive microglia in the initiation and propagation of immune responses as inflammatory mediators during inflammation in the CNS.

The acute MS lesion has been classically defined based on the presence of microglia ingesting myelin components and a lymphocyte inflammatory response. The chronic MS lesion, characteristic of the progressive phase of the disease, is dominated by the presence of activated microglia/macrophages without a prominent lymphocytic infiltrate. Human adult microglia can phagocytose myelin vesicles and secrete proinflammatory cytokines such as interleukin 1 (IL‑1), IL-6, and tumor necrosis factor α (TNF-α), and they are also known to undergo oxidative bursts. Diffuse injury of the normal-appearing white matter and cortical demyelination are classic hallmarks of primary and secondary progressive MS. The inflammation consists of mononuclear cells and diffuse infiltration of the tissue by T lymphocytes associated with profound activation of microglia.

Similar to patients with MS, the peak of disease activity in mice with experimental autoimmune encephalomyelitis (EAE)—a widely used animal model in MS—is characterized by T-cell infiltrates that decline during extended follow-up, whereas the microglia are activated persistently throughout the chronic phases. “This activation correlates well with the presence of cortical lesions, alteration of synaptic function, and axonal transport, each indicative of neuronal dysfunction,” said Dr. Khoury, Professor of Neurology at Brigham and Women’s Hospital in Boston. These data suggest that inflammation is sustained by microglia during the chronic phase of EAE.

The contribution of microglia to the progression of MS is evident in the following:
• Progressive MS correlates with the presence of diffuse axonal injury and activated microglia in the cortex and nonlesioned white matter.
• Increased expression of the major histocompatibility complex class II (MHC II) gene is found on microglia in nonlesioned white matter in the brains of patients with MS.
• Proinflammatory mediators released by microglia appear to be important contributors in blocking neurogenesis.
• Activation of microglia results in secretion of nitric oxide and proinflammatory cytokines such as IL-1, IL-6, IL-8, macrophage inflammatory protein 1-α, monocyte chemotactic protein 1, and TNF-α.
• Microglia in the subventricular zone proliferate and closely contact the neural stem cells.
Compounds that inhibit microglia activation include PPAR-γ agonists, anti-CD200 antibodies, and minocycline. PPAR-γ is a nuclear receptor that controls reproduction, metabolism, development, and immune responses. Natural and synthetic PPAR-γ agonists may control brain inflammation by inhibiting microglial activation, noted Dr. Khoury.

CD200 is expressed on neurons, and CD200R is expressed on macrophages/microglia. CD200-null mice experience an earlier onset of EAE, accompanied by an increased number and accumulation of activated macrophages and microglia in the CNS. After facial nerve transection, CD200-null mice have shown accelerated microglial response around neurons. Slow Wallerian degeneration mice have up-regulated CD200 and protection from EAE.

Minocycline has been shown to ameliorate EAE by peripheral immunomodulatory properties. Its mechanisms of action include inhibition of matrix metalloproteinase 2 activity and inhibition of inducible nitric oxide synthase, prostaglandin-E2, caspase-1, caspase-3, and cyclo-oxygenase–2 expressions, as well as the impairment of cytokine production. Some of these mechanisms are manifested, at least in part, by inhibition of mitogen-activated protein kinases. Minocycline also inhibits protein kinase C activation and decreases MHC II expression.

Optical coherence tomography is a technique that has been used to measure the thickness of the retinal nerve fiber layer and macular volume in glaucoma and other retinal diseases. These measurements provide information about the thickness of axons that emanate from the retinal ganglion cell bodies, which coalesce in the optic nerve.

Optical coherence tomography (OCT) uses infrared (IR) light to measure the thickness of the nerves in the back of the retina. The light is bounced off the retina; the way it is reflected back to a recorder at a particular point is used to develop images of the thickness of layers of the tissue at the back of the eye.

This is similar to the way ultrasound works. “It's light-based instead of sound-based,” said Dr. Peter Calabresi, director of the Multiple Sclerosis Center at Johns Hopkins University, Baltimore.

The depth of penetrance for the IR light is fairly shallow, which makes it a good technique for looking at structures and tissues right below the surface. With the latest generation of instruments, resolution is down to about 3–4 micrometers, which provides “almost a microscopic picture of the eye,” said Dr. Calabresi.

Dr. Calabresi and his colleagues have been using OCT to assess disease status in patients with multiple sclerosis. Because the retinal nerves coalesce into the optic nerve, “We know with MS that if you injure nerves in one location, that you will see downstream consequences.” Neurologists have long looked at the optic nerve head to see if it looks pale in color to determine whether the patient may have had an optic neuritis attack that led to some injury of the nerves at the back of the eye.

The retinal nerve fiber layer (RNFL) has been described as atrophying in focal/segmental patterns after an optic neuritis attack, which suggests that there were small areas of injury rather than a diffuse global process. OCT allows researchers to quantify these focal/segmental patterns of atrophy in the retinal nerve fiber layer. “This just allows us now to quantify it and to have a reproducible and reliable objective measure.”

In one study published by Dr. Calabresi and his colleagues, they compared OCT findings of the RNFL between a large cohort of MS patients and a group of healthy controls (Neurology 2007;69:2085–92). In this study, patients with MS had abnormal RNFL findings, even if they didn't have a history of optic neuritis. OCT “could then be used as a diagnostic tool to then pick up subclinical disease,” Dr. Calabresi said.

In another study, the researchers were able to show that changes in the RNFL were correlated with global brain atrophy in MS patients (Neurology 2007;69:1603–9). “By looking at this one part of the nervous system, it may be predictive of what's happening in the rest of the brain,” Dr. Calabresi said.

In the third study, they showed that the technique provides intrarater and interrater reproducibility (Arch. Neurol. 2008;65:1218–22), which is important because MS patients produce unique challenges for OCT. “Although other people have reported this in the ophthalmology world, we thought it was important to show [that] you could do this in a neurology office with MS patients,” he said. “I think it was important to show that in a patient with a more diffuse global disease, that we could get them to hold still enough to do the testing.”

There are a few caveats about OCT to consider. “The abnormalities that we look at on OCT are not specific to MS. It's very important to rule out glaucoma and other retinal processes related to hypertension or diabetes,” Dr. Calabresi said. Once a neurologist is fairly certain that the retinal abnormalities are related to MS, “it's a very useful way of tracking the disease,” said Dr. Calabresi.

OCT has some advantages over MRI—it's an office-based technique that takes about 10 minutes to perform and is much cheaper and more user-friendly than MRI. Despite this, OCT will not likely take the place of brain imaging. Dr. Calabresi sees OCT as useful in partnership with MRI.

“I imagine using it frequently in the office when the patient is coming in for a visit to directly assess the eyes and to give you some information about the status of the retinal nerves.

“We know the progressive cases tend to have more [RNFL] damage and we know that it is somewhat predictive of what is happening in the brain.”

The technique could be used in the period between brain imaging scans to assess progression.

As yet, there are no longitudinal data on the use of OCT to track progression, said Dr. Calabresi.

“What everyone wants to know is how quickly does this measurement change?” In the studies to date, patients have had their disease for about 8–10 years, and there is only about a 10-micrometer difference in RNFL thickness between MS patients and controls.

If RNFL thickness changes at a steady rate, this translates to about a micrometer per year—which falls within the margin of error. However, longitudinal data may show periods of more rapid progression and periods of relative stability, said Dr. Calabresi.

“What we're finding in OCT is that over a 2-year period, 10%-15% of people have stepwise declines of up to 10 micrometers … It's not that everyone is just losing a little bit. Some people will have subclinical attacks and not necessarily even know that they had an optic neuritis episode.”

Dr. Calabresi and his colleagues are currently working on a longitudinal study of about 1,000 patients that they've been tracking. The results are expected in the next year.

OCT is already showing promise in the clinical trial setting, where it could be used at frequent intervals to track the effectiveness of a drug on halting MS progression. The technique is being used in optic neuritis drug trials, and several companies are interested in using OCT as an assessment tool in MS trials.

Dr. Calabresi reported that he does not have any relevant conflicts of interest.

RNFL thickness map shows the right eye of an MS patient.

Areas of Red and yellow show areas of abnormality.

RNFL thickness (black line) for 0–360 degrees in right eye (top): Bottom image is a tomogram of the right eye's RNFL. Images courtesy Dr. Peter Calabresi

Optical coherence tomography is a technique that has been used to measure the thickness of the retinal nerve fiber layer and macular volume in glaucoma and other retinal diseases. These measurements provide information about the thickness of axons that emanate from the retinal ganglion cell bodies, which coalesce in the optic nerve.

Optical coherence tomography (OCT) uses infrared (IR) light to measure the thickness of the nerves in the back of the retina. The light is bounced off the retina; the way it is reflected back to a recorder at a particular point is used to develop images of the thickness of layers of the tissue at the back of the eye.

This is similar to the way ultrasound works. “It's light-based instead of sound-based,” said Dr. Peter Calabresi, director of the Multiple Sclerosis Center at Johns Hopkins University, Baltimore.

The depth of penetrance for the IR light is fairly shallow, which makes it a good technique for looking at structures and tissues right below the surface. With the latest generation of instruments, resolution is down to about 3–4 micrometers, which provides “almost a microscopic picture of the eye,” said Dr. Calabresi.

Dr. Calabresi and his colleagues have been using OCT to assess disease status in patients with multiple sclerosis. Because the retinal nerves coalesce into the optic nerve, “We know with MS that if you injure nerves in one location, that you will see downstream consequences.” Neurologists have long looked at the optic nerve head to see if it looks pale in color to determine whether the patient may have had an optic neuritis attack that led to some injury of the nerves at the back of the eye.

The retinal nerve fiber layer (RNFL) has been described as atrophying in focal/segmental patterns after an optic neuritis attack, which suggests that there were small areas of injury rather than a diffuse global process. OCT allows researchers to quantify these focal/segmental patterns of atrophy in the retinal nerve fiber layer. “This just allows us now to quantify it and to have a reproducible and reliable objective measure.”

In one study published by Dr. Calabresi and his colleagues, they compared OCT findings of the RNFL between a large cohort of MS patients and a group of healthy controls (Neurology 2007;69:2085–92). In this study, patients with MS had abnormal RNFL findings, even if they didn't have a history of optic neuritis. OCT “could then be used as a diagnostic tool to then pick up subclinical disease,” Dr. Calabresi said.

In another study, the researchers were able to show that changes in the RNFL were correlated with global brain atrophy in MS patients (Neurology 2007;69:1603–9). “By looking at this one part of the nervous system, it may be predictive of what's happening in the rest of the brain,” Dr. Calabresi said.

In the third study, they showed that the technique provides intrarater and interrater reproducibility (Arch. Neurol. 2008;65:1218–22), which is important because MS patients produce unique challenges for OCT. “Although other people have reported this in the ophthalmology world, we thought it was important to show [that] you could do this in a neurology office with MS patients,” he said. “I think it was important to show that in a patient with a more diffuse global disease, that we could get them to hold still enough to do the testing.”

There are a few caveats about OCT to consider. “The abnormalities that we look at on OCT are not specific to MS. It's very important to rule out glaucoma and other retinal processes related to hypertension or diabetes,” Dr. Calabresi said. Once a neurologist is fairly certain that the retinal abnormalities are related to MS, “it's a very useful way of tracking the disease,” said Dr. Calabresi.

OCT has some advantages over MRI—it's an office-based technique that takes about 10 minutes to perform and is much cheaper and more user-friendly than MRI. Despite this, OCT will not likely take the place of brain imaging. Dr. Calabresi sees OCT as useful in partnership with MRI.

“I imagine using it frequently in the office when the patient is coming in for a visit to directly assess the eyes and to give you some information about the status of the retinal nerves.

“We know the progressive cases tend to have more [RNFL] damage and we know that it is somewhat predictive of what is happening in the brain.”

The technique could be used in the period between brain imaging scans to assess progression.

As yet, there are no longitudinal data on the use of OCT to track progression, said Dr. Calabresi.

“What everyone wants to know is how quickly does this measurement change?” In the studies to date, patients have had their disease for about 8–10 years, and there is only about a 10-micrometer difference in RNFL thickness between MS patients and controls.

If RNFL thickness changes at a steady rate, this translates to about a micrometer per year—which falls within the margin of error. However, longitudinal data may show periods of more rapid progression and periods of relative stability, said Dr. Calabresi.

“What we're finding in OCT is that over a 2-year period, 10%-15% of people have stepwise declines of up to 10 micrometers … It's not that everyone is just losing a little bit. Some people will have subclinical attacks and not necessarily even know that they had an optic neuritis episode.”

Dr. Calabresi and his colleagues are currently working on a longitudinal study of about 1,000 patients that they've been tracking. The results are expected in the next year.

OCT is already showing promise in the clinical trial setting, where it could be used at frequent intervals to track the effectiveness of a drug on halting MS progression. The technique is being used in optic neuritis drug trials, and several companies are interested in using OCT as an assessment tool in MS trials.

Dr. Calabresi reported that he does not have any relevant conflicts of interest.

RNFL thickness map shows the right eye of an MS patient.

Areas of Red and yellow show areas of abnormality.

RNFL thickness (black line) for 0–360 degrees in right eye (top): Bottom image is a tomogram of the right eye's RNFL. Images courtesy Dr. Peter Calabresi

Optical coherence tomography is a technique that has been used to measure the thickness of the retinal nerve fiber layer and macular volume in glaucoma and other retinal diseases. These measurements provide information about the thickness of axons that emanate from the retinal ganglion cell bodies, which coalesce in the optic nerve.

Optical coherence tomography (OCT) uses infrared (IR) light to measure the thickness of the nerves in the back of the retina. The light is bounced off the retina; the way it is reflected back to a recorder at a particular point is used to develop images of the thickness of layers of the tissue at the back of the eye.

This is similar to the way ultrasound works. “It's light-based instead of sound-based,” said Dr. Peter Calabresi, director of the Multiple Sclerosis Center at Johns Hopkins University, Baltimore.

The depth of penetrance for the IR light is fairly shallow, which makes it a good technique for looking at structures and tissues right below the surface. With the latest generation of instruments, resolution is down to about 3–4 micrometers, which provides “almost a microscopic picture of the eye,” said Dr. Calabresi.

Dr. Calabresi and his colleagues have been using OCT to assess disease status in patients with multiple sclerosis. Because the retinal nerves coalesce into the optic nerve, “We know with MS that if you injure nerves in one location, that you will see downstream consequences.” Neurologists have long looked at the optic nerve head to see if it looks pale in color to determine whether the patient may have had an optic neuritis attack that led to some injury of the nerves at the back of the eye.

The retinal nerve fiber layer (RNFL) has been described as atrophying in focal/segmental patterns after an optic neuritis attack, which suggests that there were small areas of injury rather than a diffuse global process. OCT allows researchers to quantify these focal/segmental patterns of atrophy in the retinal nerve fiber layer. “This just allows us now to quantify it and to have a reproducible and reliable objective measure.”

In one study published by Dr. Calabresi and his colleagues, they compared OCT findings of the RNFL between a large cohort of MS patients and a group of healthy controls (Neurology 2007;69:2085–92). In this study, patients with MS had abnormal RNFL findings, even if they didn't have a history of optic neuritis. OCT “could then be used as a diagnostic tool to then pick up subclinical disease,” Dr. Calabresi said.

In another study, the researchers were able to show that changes in the RNFL were correlated with global brain atrophy in MS patients (Neurology 2007;69:1603–9). “By looking at this one part of the nervous system, it may be predictive of what's happening in the rest of the brain,” Dr. Calabresi said.

In the third study, they showed that the technique provides intrarater and interrater reproducibility (Arch. Neurol. 2008;65:1218–22), which is important because MS patients produce unique challenges for OCT. “Although other people have reported this in the ophthalmology world, we thought it was important to show [that] you could do this in a neurology office with MS patients,” he said. “I think it was important to show that in a patient with a more diffuse global disease, that we could get them to hold still enough to do the testing.”

There are a few caveats about OCT to consider. “The abnormalities that we look at on OCT are not specific to MS. It's very important to rule out glaucoma and other retinal processes related to hypertension or diabetes,” Dr. Calabresi said. Once a neurologist is fairly certain that the retinal abnormalities are related to MS, “it's a very useful way of tracking the disease,” said Dr. Calabresi.

OCT has some advantages over MRI—it's an office-based technique that takes about 10 minutes to perform and is much cheaper and more user-friendly than MRI. Despite this, OCT will not likely take the place of brain imaging. Dr. Calabresi sees OCT as useful in partnership with MRI.

“I imagine using it frequently in the office when the patient is coming in for a visit to directly assess the eyes and to give you some information about the status of the retinal nerves.

“We know the progressive cases tend to have more [RNFL] damage and we know that it is somewhat predictive of what is happening in the brain.”

The technique could be used in the period between brain imaging scans to assess progression.

As yet, there are no longitudinal data on the use of OCT to track progression, said Dr. Calabresi.

“What everyone wants to know is how quickly does this measurement change?” In the studies to date, patients have had their disease for about 8–10 years, and there is only about a 10-micrometer difference in RNFL thickness between MS patients and controls.

If RNFL thickness changes at a steady rate, this translates to about a micrometer per year—which falls within the margin of error. However, longitudinal data may show periods of more rapid progression and periods of relative stability, said Dr. Calabresi.

“What we're finding in OCT is that over a 2-year period, 10%-15% of people have stepwise declines of up to 10 micrometers … It's not that everyone is just losing a little bit. Some people will have subclinical attacks and not necessarily even know that they had an optic neuritis episode.”

Dr. Calabresi and his colleagues are currently working on a longitudinal study of about 1,000 patients that they've been tracking. The results are expected in the next year.

OCT is already showing promise in the clinical trial setting, where it could be used at frequent intervals to track the effectiveness of a drug on halting MS progression. The technique is being used in optic neuritis drug trials, and several companies are interested in using OCT as an assessment tool in MS trials.

Dr. Calabresi reported that he does not have any relevant conflicts of interest.

RNFL thickness map shows the right eye of an MS patient.

Areas of Red and yellow show areas of abnormality.

RNFL thickness (black line) for 0–360 degrees in right eye (top): Bottom image is a tomogram of the right eye's RNFL. Images courtesy Dr. Peter Calabresi

Elsevier Global Medical News

Elsevier Global Medical News

Elsevier Global Medical News

MADRID — High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplant may be a promising new treatment option for multiple sclerosis, based on results that were obtained in a series of 56 Russian patients.

The treatment combination improved or stabilized the condition in 92% of the patients and resulted in long-term, progression-free survival in 83%, lead investigator Dr. Yury Shevchenko reported at the annual congress of the European Federation of Neurological Societies.

He presented full data for 48 patients, all of whom had 6–30 months of follow-up (mean of 19 months).

The patients' mean age was 32 years and their mean disease duration was 7 years. Of the 56 patients, 27 had secondary progressive disease, 10 had primary progressive, 18 had relapsing-remitting disease, and 1 had progressive-relapsing disease. Their mean EDSS (Expanded Disability Status Scale) score was 6.

All patients underwent the BEAM conditioning regimen before surgery. This regimen consisted of high-dose BCNU (carmustine) at 300 mg/m2 on day 6 before the stem cell transplant; etoposide at 200 mg/m2, cytarabine at 200 mg/m2 from day 5 to day 2 before transplant, and melphalan 140 mg/m2 on the day before transplant (Exp. Hematol. 2008;36:922–8).

Patients tolerated the conditioning and transplant very well, said Dr. Shevchenko of the Pirogov National Medical Surgical Center, Moscow.

Neutropenic fever occurred in 52%; thrombocytopenia in 50%; transient increases in liver enzymes in 46%; and enteritis in 18%. There were no transplant-related deaths.

Clinical improvement (defined as a decrease on the EDSS score of at least 0.5 points) occurred in 27 patients, and stabilization occurred in 17 patients, Dr. Shevchenko said. The published study noted that nine patients had “dramatic improvement.”

One patient with secondary progressive disease and another patient with relapsing-remitting disease worsened within 6 months of the transplant but then stabilized during follow-up.

MR imaging results were available for 37 patients. Of these, 16 had active lesions at baseline, and all of these became inactive during follow-up. Of the 21 patients without active lesions at baseline, 20 remained inactive and one developed an active lesion.

There was one death, the paper noted. This patient, with secondary progressive disease, deteriorated 12 months after transplantation. About 4 years after the procedure, she developed acute promyelocytic leukemia and died of a cerebral hemorrhage.

MADRID — High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplant may be a promising new treatment option for multiple sclerosis, based on results that were obtained in a series of 56 Russian patients.

The treatment combination improved or stabilized the condition in 92% of the patients and resulted in long-term, progression-free survival in 83%, lead investigator Dr. Yury Shevchenko reported at the annual congress of the European Federation of Neurological Societies.

He presented full data for 48 patients, all of whom had 6–30 months of follow-up (mean of 19 months).

The patients' mean age was 32 years and their mean disease duration was 7 years. Of the 56 patients, 27 had secondary progressive disease, 10 had primary progressive, 18 had relapsing-remitting disease, and 1 had progressive-relapsing disease. Their mean EDSS (Expanded Disability Status Scale) score was 6.

All patients underwent the BEAM conditioning regimen before surgery. This regimen consisted of high-dose BCNU (carmustine) at 300 mg/m2 on day 6 before the stem cell transplant; etoposide at 200 mg/m2, cytarabine at 200 mg/m2 from day 5 to day 2 before transplant, and melphalan 140 mg/m2 on the day before transplant (Exp. Hematol. 2008;36:922–8).

Patients tolerated the conditioning and transplant very well, said Dr. Shevchenko of the Pirogov National Medical Surgical Center, Moscow.

Neutropenic fever occurred in 52%; thrombocytopenia in 50%; transient increases in liver enzymes in 46%; and enteritis in 18%. There were no transplant-related deaths.

Clinical improvement (defined as a decrease on the EDSS score of at least 0.5 points) occurred in 27 patients, and stabilization occurred in 17 patients, Dr. Shevchenko said. The published study noted that nine patients had “dramatic improvement.”

One patient with secondary progressive disease and another patient with relapsing-remitting disease worsened within 6 months of the transplant but then stabilized during follow-up.

MR imaging results were available for 37 patients. Of these, 16 had active lesions at baseline, and all of these became inactive during follow-up. Of the 21 patients without active lesions at baseline, 20 remained inactive and one developed an active lesion.

There was one death, the paper noted. This patient, with secondary progressive disease, deteriorated 12 months after transplantation. About 4 years after the procedure, she developed acute promyelocytic leukemia and died of a cerebral hemorrhage.

MADRID — High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplant may be a promising new treatment option for multiple sclerosis, based on results that were obtained in a series of 56 Russian patients.

The treatment combination improved or stabilized the condition in 92% of the patients and resulted in long-term, progression-free survival in 83%, lead investigator Dr. Yury Shevchenko reported at the annual congress of the European Federation of Neurological Societies.

He presented full data for 48 patients, all of whom had 6–30 months of follow-up (mean of 19 months).

The patients' mean age was 32 years and their mean disease duration was 7 years. Of the 56 patients, 27 had secondary progressive disease, 10 had primary progressive, 18 had relapsing-remitting disease, and 1 had progressive-relapsing disease. Their mean EDSS (Expanded Disability Status Scale) score was 6.

All patients underwent the BEAM conditioning regimen before surgery. This regimen consisted of high-dose BCNU (carmustine) at 300 mg/m2 on day 6 before the stem cell transplant; etoposide at 200 mg/m2, cytarabine at 200 mg/m2 from day 5 to day 2 before transplant, and melphalan 140 mg/m2 on the day before transplant (Exp. Hematol. 2008;36:922–8).

Patients tolerated the conditioning and transplant very well, said Dr. Shevchenko of the Pirogov National Medical Surgical Center, Moscow.

Neutropenic fever occurred in 52%; thrombocytopenia in 50%; transient increases in liver enzymes in 46%; and enteritis in 18%. There were no transplant-related deaths.

Clinical improvement (defined as a decrease on the EDSS score of at least 0.5 points) occurred in 27 patients, and stabilization occurred in 17 patients, Dr. Shevchenko said. The published study noted that nine patients had “dramatic improvement.”

One patient with secondary progressive disease and another patient with relapsing-remitting disease worsened within 6 months of the transplant but then stabilized during follow-up.

MR imaging results were available for 37 patients. Of these, 16 had active lesions at baseline, and all of these became inactive during follow-up. Of the 21 patients without active lesions at baseline, 20 remained inactive and one developed an active lesion.

There was one death, the paper noted. This patient, with secondary progressive disease, deteriorated 12 months after transplantation. About 4 years after the procedure, she developed acute promyelocytic leukemia and died of a cerebral hemorrhage.

Alzheimer’s Pathology Reduced With Combined Diabetes Therapy
NEW YORK, September 9 (Reuters Health)—In a postmortem study of patients with Alzheimer’s disease, diabetic subjects treated with both insulin and oral hypoglycemic agents had lower neuritic plaque densities than did other diabetics and nondiabetics, new research shows.
In several studies, type 2 diabetes has been identified as a risk factor for Alzheimer’s disease. The link between diabetes and Alzheimer’s neuropathology, by contrast, is less clear, according to the report in the September 2 issue of Neurology.
The current study, conducted by Dr. M. S. Beeri, from Mount Sinai School of Medicine in New York City, and colleagues, involved an analysis of neuritic plaques and neurofibrillary tangles in brain specimens from 124 diabetics and 124 nondiabetics.
The diabetic group consisted of 29 patients who had never used antidiabetic agents, 49 who had received insulin only, 28 treated with agents other than insulin, and 18 treated with both insulin and oral antidiabetic medications.
The overall neuritic plaque rating, the rating in the entorhinal cortex and amygdala, and the neuritic plaque count in all regions examined differed significantly among the groups. In all of the analyses, the combined medication group had fewer neuritic plaques than did the other groups.
By contrast, the authors found no significant difference in neurofibrillary tangles between the groups.
The findings provide “evidence of substantially lower neuritic plaque density in diabetic subjects taking both insulin and hypoglycemic medication consistent with the effects of both on the neurobiology of insulin,” the researchers concluded. “These pathways should be considered as potentially mechanistically important in the etiology of β amyloid–associated neuropathology and deposition of neuritic plaques.”
Neurology. 2008;71(10):750-757.
Antiepileptic Drug Use May Contribute to Bone Loss in Older Men
NEW YORK, September 19 (Reuters Health)—Use of non–enzyme-inducing antiepileptic drugs (AEDs) independently raises the risk of bone loss at the hip in older men, results of a prospective study suggest.
In the September 2 issue of Neurology, Dr. Kristine E. Ensrud, from the Veterans Affairs Medical Center in Minneapolis, and colleagues pointed out, “AED use may be associated with higher rates of bone loss because [the drugs] may have adverse effects on bone metabolism. On the other hand, AED use may be a marker of factors such as poor health ... that are associated with greater rates of bone loss.”
In 4,222 older community-dwelling participants in the Osteoporosis Fractures in Men study, the researchers analyzed use of non–enzyme-inducing and enzyme-inducing AEDs. They also measured subjects’ hip bone mineral density (BMD) at baseline and at an average of 4.6 years later.
Among men who didn’t use AEDs at all, the average rate of decline in total hip BMD per year was -0.35%, compared with -0.46% among enzyme-inducing AED users and -0.53% among non–enzyme-inducing AED users.
The rate of loss per year was -0.60% among men who were taking non–enzyme-inducing AEDs at both examinations, -0.51% among men taking non–enzyme-inducing AEDs at one examination only, and -0.35% among nonusers.
The researchers pointed out that these findings were achieved after adjustment for a myriad of potential confounders not accounted for in past studies, including age, race, health status, baseline BMD, physical activity, smoking, alcohol intake, total calcium intake, diabetes, kidney disease, bisphosphonate or SSRI use, and BMI.
“Our results suggest that non–enzyme-inducing AED use is associated in a graded manner with rates of hip bone loss in older men, with lower rates of loss among nonusers of AEDs, intermediate rates of loss among intermittent users, and high rates of loss among continuous users,” the authors wrote.
They added, “These findings are supported by prior studies reporting higher fracture rates among non–enzyme-inducing AED users compared with nonusers of AEDs or a similar fracture risk between patients taking non–enzyme-inducing AEDs versus those taking enzyme-inducing AEDs.”
In particular, the results suggest that men who take gabapentin have a 1.4- to 1.8-fold higher adjusted rate of bone loss at the hip compared with nonusers of AEDs.
Neurology. 2008;71(10):723-730.
Relatives of Patients With Brain Tumors Seem to Be at Increased Risk
NEW YORK, September 22 (Reu­ters Health)—By linking a Utah genealogy database to statewide cancer records, researchers have uncovered evidence of a familial contribution to primary brain cancer risk.
“There has been landmark work done previously using the Utah Population Database resource, in discovering hereditary associations and specific genes for breast cancer, colon cancer, and other nonneoplastic diseases,” Dr. Deborah T. Blumenthal told Reuters Health. “We sought to utilize this unique resource to search for familial relationships in primary brain tumors.”
The database includes more than two million persons with up to 10 generations of genealogic data. Dr. Blumenthal, currently at Tel-Aviv Sourasky Medical Center, and Dr. Lisa A. Cannon-Albright, at the University of Utah in Salt Lake City, examined the risk of brain tumors in the relatives of 744 individuals with astrocytoma, 658 patients with glioblastoma, and one patient with both.
According to their report in the September 23 issue of Neurology, significant excess risk exists among first-degree relatives of patients with astrocytoma or glioblastoma, compared with the rate of disease in the general population.
There was also significantly increased risk among second-degree relatives of patients with astrocytoma.
Noting that cancers with a genetic contribution often occur at an earlier age than sporadic cases, the researchers report that first-degree relatives of patients diagnosed before age 20 were at higher risk. Risk was also elevated for family members of cases with astrocytoma diagnosed before age 15.
“These findings, which remained significant beyond first-degree relations, support the hypothesis of familiality—a common gene or group of genes that may predispose individuals to brain tumors,” Dr. Blumenthal said.
“It needs to be stressed that we are still considering a very small minority (less than 5%) of an already small group of patients (less than 20,000/year in the US) who may have a familial risk for being affected with these tumors,” she added. “However, clinicians should be aware of this association and carefully query family history in their patients. If other family members have neurologic symptoms, the threshold for screening them for a brain tumor should be lower.”
Such symptoms, she explained, may include “new, progressive headaches, nausea or vomiting, seizures (which may be motor or sensory phenomenon, or even episodes of odd smells/tastes or déjà vu, when the temporal lobe is involved), changes in vision, changes in speech or language ability (word-finding difficulty), changes in personality (including apathy or apparent depression), and imbalance or incoordination.”

The researchers now plan prospective follow-up of these high-risk pedigrees.
“If genes or loci responsible for brain tumors could be identified, they could have relevance not only for familial tumors, but for the larger population as well,” Dr. Blumenthal concluded. “Ultimately, with such information, screening and even preventive therapy for malignant brain tumors might be possible in the future.”
Neurology. 2008;71(13):1015-1020.
Engerix B Vaccine May Increase the Risk of Multiple Sclerosis in Children
NEW YORK, September 26 (Reuters Health)—Although most hepatitis B vaccines do not seem to increase the risk of multiple sclerosis (MS) in children, use of one particular brand—Engerix B (GlaxoSmithKline)—may, according to findings from a study conducted in France.
In the study reported in the October 8 online issue of Neurology, the odds ratio (OR) for Engerix B exposure was 2.77 among children with MS, compared with an unaffected control group.
Prior reports have suggested a link between hepatitis B vaccine exposure and CNS inflammatory demyelination, including MS as well as acute disseminated encephalomyelitis and transverse myelitis. In general, however, findings from epidemiologic studies have not supported an association.
The focus of the current case-control study was on the neurologic effects of hepatitis B vaccination in children, since most of the prior investigations involved adults only, lead author Dr. Yann Mikaeloff, from Assistance Publique-Hôpitaux de Paris, and colleagues noted.
Case patients included 349 children with a first episode of CNS inflammatory demyelination between 1994 and 2003. Each subject was matched to up to 12 controls by age, gender, and geographic location.
In the overall analysis, hepatitis B vaccination did not increase the risk of CNS inflammatory demyelination.
However, when the analysis was confined to vaccine-compliant subjects, vaccine exposure more than three years prior to the index date was linked to an elevated risk (OR, 1.50). Further analysis showed that this association was mostly driven by the risk seen with Engerix B use (OR, 1.74).
Vaccine exposure more than three years before the index date was tied to a 2.12-fold increased risk of confirmed MS. Once again, however, this was mostly accounted for by Engerix B use (OR,  2.77).
As to why one brand of hepatitis B vaccine is safe while another may not be, the authors offer two possible explanations: “(1) each vaccine uses a different section of the hepatitis B antigen, and some protein fragments produced by yeasts may induce molecular mimicry, while others do not; (2) the production process varies by brand, and differences in yeast protein content may be crucial if yeast protein may trigger autoimmune reactions.”
The packaging insert (December 2006) for Engerix B mentions reports of patients with MS who experience exacerbations following use of the vaccine, but it points out that causality has not been established. The insert also notes new cases of MS and transverse myelitis that occurred after vaccination and were identified during postmarketing surveillance.
Neurology. 2008 Oct 8; [Epub ahead of print].

Alzheimer’s Pathology Reduced With Combined Diabetes Therapy
NEW YORK, September 9 (Reuters Health)—In a postmortem study of patients with Alzheimer’s disease, diabetic subjects treated with both insulin and oral hypoglycemic agents had lower neuritic plaque densities than did other diabetics and nondiabetics, new research shows.
In several studies, type 2 diabetes has been identified as a risk factor for Alzheimer’s disease. The link between diabetes and Alzheimer’s neuropathology, by contrast, is less clear, according to the report in the September 2 issue of Neurology.
The current study, conducted by Dr. M. S. Beeri, from Mount Sinai School of Medicine in New York City, and colleagues, involved an analysis of neuritic plaques and neurofibrillary tangles in brain specimens from 124 diabetics and 124 nondiabetics.
The diabetic group consisted of 29 patients who had never used antidiabetic agents, 49 who had received insulin only, 28 treated with agents other than insulin, and 18 treated with both insulin and oral antidiabetic medications.
The overall neuritic plaque rating, the rating in the entorhinal cortex and amygdala, and the neuritic plaque count in all regions examined differed significantly among the groups. In all of the analyses, the combined medication group had fewer neuritic plaques than did the other groups.
By contrast, the authors found no significant difference in neurofibrillary tangles between the groups.
The findings provide “evidence of substantially lower neuritic plaque density in diabetic subjects taking both insulin and hypoglycemic medication consistent with the effects of both on the neurobiology of insulin,” the researchers concluded. “These pathways should be considered as potentially mechanistically important in the etiology of β amyloid–associated neuropathology and deposition of neuritic plaques.”
Neurology. 2008;71(10):750-757.
Antiepileptic Drug Use May Contribute to Bone Loss in Older Men
NEW YORK, September 19 (Reuters Health)—Use of non–enzyme-inducing antiepileptic drugs (AEDs) independently raises the risk of bone loss at the hip in older men, results of a prospective study suggest.
In the September 2 issue of Neurology, Dr. Kristine E. Ensrud, from the Veterans Affairs Medical Center in Minneapolis, and colleagues pointed out, “AED use may be associated with higher rates of bone loss because [the drugs] may have adverse effects on bone metabolism. On the other hand, AED use may be a marker of factors such as poor health ... that are associated with greater rates of bone loss.”
In 4,222 older community-dwelling participants in the Osteoporosis Fractures in Men study, the researchers analyzed use of non–enzyme-inducing and enzyme-inducing AEDs. They also measured subjects’ hip bone mineral density (BMD) at baseline and at an average of 4.6 years later.
Among men who didn’t use AEDs at all, the average rate of decline in total hip BMD per year was -0.35%, compared with -0.46% among enzyme-inducing AED users and -0.53% among non–enzyme-inducing AED users.
The rate of loss per year was -0.60% among men who were taking non–enzyme-inducing AEDs at both examinations, -0.51% among men taking non–enzyme-inducing AEDs at one examination only, and -0.35% among nonusers.
The researchers pointed out that these findings were achieved after adjustment for a myriad of potential confounders not accounted for in past studies, including age, race, health status, baseline BMD, physical activity, smoking, alcohol intake, total calcium intake, diabetes, kidney disease, bisphosphonate or SSRI use, and BMI.
“Our results suggest that non–enzyme-inducing AED use is associated in a graded manner with rates of hip bone loss in older men, with lower rates of loss among nonusers of AEDs, intermediate rates of loss among intermittent users, and high rates of loss among continuous users,” the authors wrote.
They added, “These findings are supported by prior studies reporting higher fracture rates among non–enzyme-inducing AED users compared with nonusers of AEDs or a similar fracture risk between patients taking non–enzyme-inducing AEDs versus those taking enzyme-inducing AEDs.”
In particular, the results suggest that men who take gabapentin have a 1.4- to 1.8-fold higher adjusted rate of bone loss at the hip compared with nonusers of AEDs.
Neurology. 2008;71(10):723-730.
Relatives of Patients With Brain Tumors Seem to Be at Increased Risk
NEW YORK, September 22 (Reu­ters Health)—By linking a Utah genealogy database to statewide cancer records, researchers have uncovered evidence of a familial contribution to primary brain cancer risk.
“There has been landmark work done previously using the Utah Population Database resource, in discovering hereditary associations and specific genes for breast cancer, colon cancer, and other nonneoplastic diseases,” Dr. Deborah T. Blumenthal told Reuters Health. “We sought to utilize this unique resource to search for familial relationships in primary brain tumors.”
The database includes more than two million persons with up to 10 generations of genealogic data. Dr. Blumenthal, currently at Tel-Aviv Sourasky Medical Center, and Dr. Lisa A. Cannon-Albright, at the University of Utah in Salt Lake City, examined the risk of brain tumors in the relatives of 744 individuals with astrocytoma, 658 patients with glioblastoma, and one patient with both.
According to their report in the September 23 issue of Neurology, significant excess risk exists among first-degree relatives of patients with astrocytoma or glioblastoma, compared with the rate of disease in the general population.
There was also significantly increased risk among second-degree relatives of patients with astrocytoma.
Noting that cancers with a genetic contribution often occur at an earlier age than sporadic cases, the researchers report that first-degree relatives of patients diagnosed before age 20 were at higher risk. Risk was also elevated for family members of cases with astrocytoma diagnosed before age 15.
“These findings, which remained significant beyond first-degree relations, support the hypothesis of familiality—a common gene or group of genes that may predispose individuals to brain tumors,” Dr. Blumenthal said.
“It needs to be stressed that we are still considering a very small minority (less than 5%) of an already small group of patients (less than 20,000/year in the US) who may have a familial risk for being affected with these tumors,” she added. “However, clinicians should be aware of this association and carefully query family history in their patients. If other family members have neurologic symptoms, the threshold for screening them for a brain tumor should be lower.”
Such symptoms, she explained, may include “new, progressive headaches, nausea or vomiting, seizures (which may be motor or sensory phenomenon, or even episodes of odd smells/tastes or déjà vu, when the temporal lobe is involved), changes in vision, changes in speech or language ability (word-finding difficulty), changes in personality (including apathy or apparent depression), and imbalance or incoordination.”

The researchers now plan prospective follow-up of these high-risk pedigrees.
“If genes or loci responsible for brain tumors could be identified, they could have relevance not only for familial tumors, but for the larger population as well,” Dr. Blumenthal concluded. “Ultimately, with such information, screening and even preventive therapy for malignant brain tumors might be possible in the future.”
Neurology. 2008;71(13):1015-1020.
Engerix B Vaccine May Increase the Risk of Multiple Sclerosis in Children
NEW YORK, September 26 (Reuters Health)—Although most hepatitis B vaccines do not seem to increase the risk of multiple sclerosis (MS) in children, use of one particular brand—Engerix B (GlaxoSmithKline)—may, according to findings from a study conducted in France.
In the study reported in the October 8 online issue of Neurology, the odds ratio (OR) for Engerix B exposure was 2.77 among children with MS, compared with an unaffected control group.
Prior reports have suggested a link between hepatitis B vaccine exposure and CNS inflammatory demyelination, including MS as well as acute disseminated encephalomyelitis and transverse myelitis. In general, however, findings from epidemiologic studies have not supported an association.
The focus of the current case-control study was on the neurologic effects of hepatitis B vaccination in children, since most of the prior investigations involved adults only, lead author Dr. Yann Mikaeloff, from Assistance Publique-Hôpitaux de Paris, and colleagues noted.
Case patients included 349 children with a first episode of CNS inflammatory demyelination between 1994 and 2003. Each subject was matched to up to 12 controls by age, gender, and geographic location.
In the overall analysis, hepatitis B vaccination did not increase the risk of CNS inflammatory demyelination.
However, when the analysis was confined to vaccine-compliant subjects, vaccine exposure more than three years prior to the index date was linked to an elevated risk (OR, 1.50). Further analysis showed that this association was mostly driven by the risk seen with Engerix B use (OR, 1.74).
Vaccine exposure more than three years before the index date was tied to a 2.12-fold increased risk of confirmed MS. Once again, however, this was mostly accounted for by Engerix B use (OR,  2.77).
As to why one brand of hepatitis B vaccine is safe while another may not be, the authors offer two possible explanations: “(1) each vaccine uses a different section of the hepatitis B antigen, and some protein fragments produced by yeasts may induce molecular mimicry, while others do not; (2) the production process varies by brand, and differences in yeast protein content may be crucial if yeast protein may trigger autoimmune reactions.”
The packaging insert (December 2006) for Engerix B mentions reports of patients with MS who experience exacerbations following use of the vaccine, but it points out that causality has not been established. The insert also notes new cases of MS and transverse myelitis that occurred after vaccination and were identified during postmarketing surveillance.
Neurology. 2008 Oct 8; [Epub ahead of print].

Alzheimer’s Pathology Reduced With Combined Diabetes Therapy
NEW YORK, September 9 (Reuters Health)—In a postmortem study of patients with Alzheimer’s disease, diabetic subjects treated with both insulin and oral hypoglycemic agents had lower neuritic plaque densities than did other diabetics and nondiabetics, new research shows.
In several studies, type 2 diabetes has been identified as a risk factor for Alzheimer’s disease. The link between diabetes and Alzheimer’s neuropathology, by contrast, is less clear, according to the report in the September 2 issue of Neurology.
The current study, conducted by Dr. M. S. Beeri, from Mount Sinai School of Medicine in New York City, and colleagues, involved an analysis of neuritic plaques and neurofibrillary tangles in brain specimens from 124 diabetics and 124 nondiabetics.
The diabetic group consisted of 29 patients who had never used antidiabetic agents, 49 who had received insulin only, 28 treated with agents other than insulin, and 18 treated with both insulin and oral antidiabetic medications.
The overall neuritic plaque rating, the rating in the entorhinal cortex and amygdala, and the neuritic plaque count in all regions examined differed significantly among the groups. In all of the analyses, the combined medication group had fewer neuritic plaques than did the other groups.
By contrast, the authors found no significant difference in neurofibrillary tangles between the groups.
The findings provide “evidence of substantially lower neuritic plaque density in diabetic subjects taking both insulin and hypoglycemic medication consistent with the effects of both on the neurobiology of insulin,” the researchers concluded. “These pathways should be considered as potentially mechanistically important in the etiology of β amyloid–associated neuropathology and deposition of neuritic plaques.”
Neurology. 2008;71(10):750-757.
Antiepileptic Drug Use May Contribute to Bone Loss in Older Men
NEW YORK, September 19 (Reuters Health)—Use of non–enzyme-inducing antiepileptic drugs (AEDs) independently raises the risk of bone loss at the hip in older men, results of a prospective study suggest.
In the September 2 issue of Neurology, Dr. Kristine E. Ensrud, from the Veterans Affairs Medical Center in Minneapolis, and colleagues pointed out, “AED use may be associated with higher rates of bone loss because [the drugs] may have adverse effects on bone metabolism. On the other hand, AED use may be a marker of factors such as poor health ... that are associated with greater rates of bone loss.”
In 4,222 older community-dwelling participants in the Osteoporosis Fractures in Men study, the researchers analyzed use of non–enzyme-inducing and enzyme-inducing AEDs. They also measured subjects’ hip bone mineral density (BMD) at baseline and at an average of 4.6 years later.
Among men who didn’t use AEDs at all, the average rate of decline in total hip BMD per year was -0.35%, compared with -0.46% among enzyme-inducing AED users and -0.53% among non–enzyme-inducing AED users.
The rate of loss per year was -0.60% among men who were taking non–enzyme-inducing AEDs at both examinations, -0.51% among men taking non–enzyme-inducing AEDs at one examination only, and -0.35% among nonusers.
The researchers pointed out that these findings were achieved after adjustment for a myriad of potential confounders not accounted for in past studies, including age, race, health status, baseline BMD, physical activity, smoking, alcohol intake, total calcium intake, diabetes, kidney disease, bisphosphonate or SSRI use, and BMI.
“Our results suggest that non–enzyme-inducing AED use is associated in a graded manner with rates of hip bone loss in older men, with lower rates of loss among nonusers of AEDs, intermediate rates of loss among intermittent users, and high rates of loss among continuous users,” the authors wrote.
They added, “These findings are supported by prior studies reporting higher fracture rates among non–enzyme-inducing AED users compared with nonusers of AEDs or a similar fracture risk between patients taking non–enzyme-inducing AEDs versus those taking enzyme-inducing AEDs.”
In particular, the results suggest that men who take gabapentin have a 1.4- to 1.8-fold higher adjusted rate of bone loss at the hip compared with nonusers of AEDs.
Neurology. 2008;71(10):723-730.
Relatives of Patients With Brain Tumors Seem to Be at Increased Risk
NEW YORK, September 22 (Reu­ters Health)—By linking a Utah genealogy database to statewide cancer records, researchers have uncovered evidence of a familial contribution to primary brain cancer risk.
“There has been landmark work done previously using the Utah Population Database resource, in discovering hereditary associations and specific genes for breast cancer, colon cancer, and other nonneoplastic diseases,” Dr. Deborah T. Blumenthal told Reuters Health. “We sought to utilize this unique resource to search for familial relationships in primary brain tumors.”
The database includes more than two million persons with up to 10 generations of genealogic data. Dr. Blumenthal, currently at Tel-Aviv Sourasky Medical Center, and Dr. Lisa A. Cannon-Albright, at the University of Utah in Salt Lake City, examined the risk of brain tumors in the relatives of 744 individuals with astrocytoma, 658 patients with glioblastoma, and one patient with both.
According to their report in the September 23 issue of Neurology, significant excess risk exists among first-degree relatives of patients with astrocytoma or glioblastoma, compared with the rate of disease in the general population.
There was also significantly increased risk among second-degree relatives of patients with astrocytoma.
Noting that cancers with a genetic contribution often occur at an earlier age than sporadic cases, the researchers report that first-degree relatives of patients diagnosed before age 20 were at higher risk. Risk was also elevated for family members of cases with astrocytoma diagnosed before age 15.
“These findings, which remained significant beyond first-degree relations, support the hypothesis of familiality—a common gene or group of genes that may predispose individuals to brain tumors,” Dr. Blumenthal said.
“It needs to be stressed that we are still considering a very small minority (less than 5%) of an already small group of patients (less than 20,000/year in the US) who may have a familial risk for being affected with these tumors,” she added. “However, clinicians should be aware of this association and carefully query family history in their patients. If other family members have neurologic symptoms, the threshold for screening them for a brain tumor should be lower.”
Such symptoms, she explained, may include “new, progressive headaches, nausea or vomiting, seizures (which may be motor or sensory phenomenon, or even episodes of odd smells/tastes or déjà vu, when the temporal lobe is involved), changes in vision, changes in speech or language ability (word-finding difficulty), changes in personality (including apathy or apparent depression), and imbalance or incoordination.”

The researchers now plan prospective follow-up of these high-risk pedigrees.
“If genes or loci responsible for brain tumors could be identified, they could have relevance not only for familial tumors, but for the larger population as well,” Dr. Blumenthal concluded. “Ultimately, with such information, screening and even preventive therapy for malignant brain tumors might be possible in the future.”
Neurology. 2008;71(13):1015-1020.
Engerix B Vaccine May Increase the Risk of Multiple Sclerosis in Children
NEW YORK, September 26 (Reuters Health)—Although most hepatitis B vaccines do not seem to increase the risk of multiple sclerosis (MS) in children, use of one particular brand—Engerix B (GlaxoSmithKline)—may, according to findings from a study conducted in France.
In the study reported in the October 8 online issue of Neurology, the odds ratio (OR) for Engerix B exposure was 2.77 among children with MS, compared with an unaffected control group.
Prior reports have suggested a link between hepatitis B vaccine exposure and CNS inflammatory demyelination, including MS as well as acute disseminated encephalomyelitis and transverse myelitis. In general, however, findings from epidemiologic studies have not supported an association.
The focus of the current case-control study was on the neurologic effects of hepatitis B vaccination in children, since most of the prior investigations involved adults only, lead author Dr. Yann Mikaeloff, from Assistance Publique-Hôpitaux de Paris, and colleagues noted.
Case patients included 349 children with a first episode of CNS inflammatory demyelination between 1994 and 2003. Each subject was matched to up to 12 controls by age, gender, and geographic location.
In the overall analysis, hepatitis B vaccination did not increase the risk of CNS inflammatory demyelination.
However, when the analysis was confined to vaccine-compliant subjects, vaccine exposure more than three years prior to the index date was linked to an elevated risk (OR, 1.50). Further analysis showed that this association was mostly driven by the risk seen with Engerix B use (OR, 1.74).
Vaccine exposure more than three years before the index date was tied to a 2.12-fold increased risk of confirmed MS. Once again, however, this was mostly accounted for by Engerix B use (OR,  2.77).
As to why one brand of hepatitis B vaccine is safe while another may not be, the authors offer two possible explanations: “(1) each vaccine uses a different section of the hepatitis B antigen, and some protein fragments produced by yeasts may induce molecular mimicry, while others do not; (2) the production process varies by brand, and differences in yeast protein content may be crucial if yeast protein may trigger autoimmune reactions.”
The packaging insert (December 2006) for Engerix B mentions reports of patients with MS who experience exacerbations following use of the vaccine, but it points out that causality has not been established. The insert also notes new cases of MS and transverse myelitis that occurred after vaccination and were identified during postmarketing surveillance.
Neurology. 2008 Oct 8; [Epub ahead of print].

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

Intermittent, add-on treatment with an oral corticosteroid led to a significant drop in relapses among patients with multiple sclerosis who were previously relapsing on monotherapy with interferon-β in a controlled study with 130 patients.

If the efficacy of this cyclic regimen with methylprednisolone is confirmed in a second study now in progress, add-on, cyclic treatment with methylprednisolone “would be justified as routine therapy,” said Dr. Per Soelberg Sørensen, who reported his finding at the World Congress on Treatment and Research in Multiple Sclerosis in Montreal.

Cyclic treatment with methylprednisolone as an add-on to interferon, mitoxantrone, or cyclophosphamide already is used off label at many multiple sclerosis (MS) clinics, said Dr. Sørensen, a professor in the department of clinical neuroscience and psychiatry at Rigshospitalet, Copenhagen.

The Nordic trial of methylprednisolone as add-on therapy to interferon-β (IFN-β) for the treatment of relapsing-remitting multiple sclerosis (NORMIMS), run by Dr. Sørensen and his associates at seven centers in Scandinavia, enrolled MS patients on long-term, subcutaneous treatment with interferon beta-1a who had at least one relapse during their previous year on treatment. In general, about 35% of MS patients on long-term treatment with IFN-β have relapses. The average relapse rate for all MS patients on a steady interferon regimen is 0.4 relapse events per year, Dr. Sørensen said in an interview.

The patients were randomized to receive either placebo or 200 mg of oral methylprednisolone daily for 5 days at 4 week intervals (a total monthly dose of 1 g). During the study, the interferon beta-1a regimen was maintained at a dosage of 44 mcg administered subcutaneously three times a week.

During 96 weeks of treatment, the annualized relapse rate of the 66 patients on methylprednisolone was 22%, compared with a 59% relapse rate among the 64 control patients on placebo, a statistically significant difference, said Dr. Sørensen.

During the study, 8 patients on methylprednisolone and 14 patients on placebo had a sustained increased in their disability based on at least a 1-point rise in their expanded disability status score. The average time it took for patients to have a sustained increase in their disability was 626 days for the patients on methylprednisolone and 376 days among those in the placebo group. The average number of active MS lesions seen with MRI in each patient during 1 year was 4.8 in those on the oral steroid and 5.4 in the control patients, a difference that just reached statistical significance. Methylprednisolone therapy was also well tolerated.

If methylprednisolone was used as cyclic, add-on therapy with IFN-β in routine practice, patients who failed to respond satisfactorily to the combination should be switched to other agents. Natalizumab and mitoxantrone are both approved as second-line drugs for MS and would be alternatives to consider, Dr. Sørensen said.

The second study of methylprednisolone added to interferon beta-1a in relapsing MS patients has treated more than 150 patients with the combination for 3 years. The methylprednisolone dosage used was higher, 500 mg/day for 3 days every 4 weeks (1.5 g/month), the maximum tolerable dose for this steroid, Dr. Sørensen said.

Results from this second study should be reported soon, according to Dr. Sørensen, who is also a coinvestigator for the second study.

Intermittent, add-on treatment with an oral corticosteroid led to a significant drop in relapses among patients with multiple sclerosis who were previously relapsing on monotherapy with interferon-β in a controlled study with 130 patients.

If the efficacy of this cyclic regimen with methylprednisolone is confirmed in a second study now in progress, add-on, cyclic treatment with methylprednisolone “would be justified as routine therapy,” said Dr. Per Soelberg Sørensen, who reported his finding at the World Congress on Treatment and Research in Multiple Sclerosis in Montreal.

Cyclic treatment with methylprednisolone as an add-on to interferon, mitoxantrone, or cyclophosphamide already is used off label at many multiple sclerosis (MS) clinics, said Dr. Sørensen, a professor in the department of clinical neuroscience and psychiatry at Rigshospitalet, Copenhagen.

The Nordic trial of methylprednisolone as add-on therapy to interferon-β (IFN-β) for the treatment of relapsing-remitting multiple sclerosis (NORMIMS), run by Dr. Sørensen and his associates at seven centers in Scandinavia, enrolled MS patients on long-term, subcutaneous treatment with interferon beta-1a who had at least one relapse during their previous year on treatment. In general, about 35% of MS patients on long-term treatment with IFN-β have relapses. The average relapse rate for all MS patients on a steady interferon regimen is 0.4 relapse events per year, Dr. Sørensen said in an interview.

The patients were randomized to receive either placebo or 200 mg of oral methylprednisolone daily for 5 days at 4 week intervals (a total monthly dose of 1 g). During the study, the interferon beta-1a regimen was maintained at a dosage of 44 mcg administered subcutaneously three times a week.

During 96 weeks of treatment, the annualized relapse rate of the 66 patients on methylprednisolone was 22%, compared with a 59% relapse rate among the 64 control patients on placebo, a statistically significant difference, said Dr. Sørensen.

During the study, 8 patients on methylprednisolone and 14 patients on placebo had a sustained increased in their disability based on at least a 1-point rise in their expanded disability status score. The average time it took for patients to have a sustained increase in their disability was 626 days for the patients on methylprednisolone and 376 days among those in the placebo group. The average number of active MS lesions seen with MRI in each patient during 1 year was 4.8 in those on the oral steroid and 5.4 in the control patients, a difference that just reached statistical significance. Methylprednisolone therapy was also well tolerated.

If methylprednisolone was used as cyclic, add-on therapy with IFN-β in routine practice, patients who failed to respond satisfactorily to the combination should be switched to other agents. Natalizumab and mitoxantrone are both approved as second-line drugs for MS and would be alternatives to consider, Dr. Sørensen said.

The second study of methylprednisolone added to interferon beta-1a in relapsing MS patients has treated more than 150 patients with the combination for 3 years. The methylprednisolone dosage used was higher, 500 mg/day for 3 days every 4 weeks (1.5 g/month), the maximum tolerable dose for this steroid, Dr. Sørensen said.

Results from this second study should be reported soon, according to Dr. Sørensen, who is also a coinvestigator for the second study.

Intermittent, add-on treatment with an oral corticosteroid led to a significant drop in relapses among patients with multiple sclerosis who were previously relapsing on monotherapy with interferon-β in a controlled study with 130 patients.

If the efficacy of this cyclic regimen with methylprednisolone is confirmed in a second study now in progress, add-on, cyclic treatment with methylprednisolone “would be justified as routine therapy,” said Dr. Per Soelberg Sørensen, who reported his finding at the World Congress on Treatment and Research in Multiple Sclerosis in Montreal.

Cyclic treatment with methylprednisolone as an add-on to interferon, mitoxantrone, or cyclophosphamide already is used off label at many multiple sclerosis (MS) clinics, said Dr. Sørensen, a professor in the department of clinical neuroscience and psychiatry at Rigshospitalet, Copenhagen.

The Nordic trial of methylprednisolone as add-on therapy to interferon-β (IFN-β) for the treatment of relapsing-remitting multiple sclerosis (NORMIMS), run by Dr. Sørensen and his associates at seven centers in Scandinavia, enrolled MS patients on long-term, subcutaneous treatment with interferon beta-1a who had at least one relapse during their previous year on treatment. In general, about 35% of MS patients on long-term treatment with IFN-β have relapses. The average relapse rate for all MS patients on a steady interferon regimen is 0.4 relapse events per year, Dr. Sørensen said in an interview.

The patients were randomized to receive either placebo or 200 mg of oral methylprednisolone daily for 5 days at 4 week intervals (a total monthly dose of 1 g). During the study, the interferon beta-1a regimen was maintained at a dosage of 44 mcg administered subcutaneously three times a week.

During 96 weeks of treatment, the annualized relapse rate of the 66 patients on methylprednisolone was 22%, compared with a 59% relapse rate among the 64 control patients on placebo, a statistically significant difference, said Dr. Sørensen.

During the study, 8 patients on methylprednisolone and 14 patients on placebo had a sustained increased in their disability based on at least a 1-point rise in their expanded disability status score. The average time it took for patients to have a sustained increase in their disability was 626 days for the patients on methylprednisolone and 376 days among those in the placebo group. The average number of active MS lesions seen with MRI in each patient during 1 year was 4.8 in those on the oral steroid and 5.4 in the control patients, a difference that just reached statistical significance. Methylprednisolone therapy was also well tolerated.

If methylprednisolone was used as cyclic, add-on therapy with IFN-β in routine practice, patients who failed to respond satisfactorily to the combination should be switched to other agents. Natalizumab and mitoxantrone are both approved as second-line drugs for MS and would be alternatives to consider, Dr. Sørensen said.

The second study of methylprednisolone added to interferon beta-1a in relapsing MS patients has treated more than 150 patients with the combination for 3 years. The methylprednisolone dosage used was higher, 500 mg/day for 3 days every 4 weeks (1.5 g/month), the maximum tolerable dose for this steroid, Dr. Sørensen said.

Results from this second study should be reported soon, according to Dr. Sørensen, who is also a coinvestigator for the second study.

CHICAGO—Many of the neuropsychologic tests that target cognitive domains affected in patients with multiple sclerosis (MS) do not appear to be predictive of neuropsychiatric symptoms in these patients, as has been previously hypothesized, reported Jesus Lovera, PhD, and colleagues. Neuropsychiatric symptoms occur in 80% of patients with MS, and depression is the most common of these symptoms, the researchers stated at the 60th Annual Meeting of the American Academy of Neurology.

The investigators studied 109 patients (mean age, 51) who were enrolled in clinical trials of memantine for cognitive impairment in MS. Among the inclusion criteria were significant cognitive complaints, a score 1 SD below the normal population average on the Paced Auditory Serial Addition Test (PASAT) or the California Verbal Learning Test-II (CVLT-II), and a Beck Depression Inventory–IA score of less than 19.

Neuropsychologic tests included a three-second version of the PASAT, the CVLT-II, the Symbol Digits Modalities Test, the Delis-Kaplan Executive Function System (D-KEFS) sorting test, the Controlled Oral Word Association Test (COWAT), and the Victoria version of the Stroop test. Neuropsychiatric symptoms were assessed using the Modified Neuropsychiatric Inventory.

According to Dr. Lovera, who is an Instructor in the Department of Neurology at Oregon Health and Science University in Portland, and colleagues, 55 patients had one or more neuropsychiatric symptoms: 42 had irritability, 31 anxiety, 24 agitation/aggression, 23 apathy, 18 disinhibition, and 11 euphoria. Tests of attention and processing speed (PASAT), verbal fluency (COWAT), sorting (D-KEFS), and verbal learning and recall (CVLT-II) were not predictive of neuropsychiatric symptoms.

Perseveration and intrusions, as measured by the Stroop test and the CVLT-II, were highly predictive of neuropsychiatric symptoms.

Physicians should consider screening for neuropsychiatric symptoms in patients with MS, particularly in those with cognitive complaints, commented the researchers. They also advised that patients with MS who have impairment on the Stroop test or intrusions or repetitions on the CVLT-II be screened for neuropsychiatric symptoms.

CHICAGO—Many of the neuropsychologic tests that target cognitive domains affected in patients with multiple sclerosis (MS) do not appear to be predictive of neuropsychiatric symptoms in these patients, as has been previously hypothesized, reported Jesus Lovera, PhD, and colleagues. Neuropsychiatric symptoms occur in 80% of patients with MS, and depression is the most common of these symptoms, the researchers stated at the 60th Annual Meeting of the American Academy of Neurology.

The investigators studied 109 patients (mean age, 51) who were enrolled in clinical trials of memantine for cognitive impairment in MS. Among the inclusion criteria were significant cognitive complaints, a score 1 SD below the normal population average on the Paced Auditory Serial Addition Test (PASAT) or the California Verbal Learning Test-II (CVLT-II), and a Beck Depression Inventory–IA score of less than 19.

Neuropsychologic tests included a three-second version of the PASAT, the CVLT-II, the Symbol Digits Modalities Test, the Delis-Kaplan Executive Function System (D-KEFS) sorting test, the Controlled Oral Word Association Test (COWAT), and the Victoria version of the Stroop test. Neuropsychiatric symptoms were assessed using the Modified Neuropsychiatric Inventory.

According to Dr. Lovera, who is an Instructor in the Department of Neurology at Oregon Health and Science University in Portland, and colleagues, 55 patients had one or more neuropsychiatric symptoms: 42 had irritability, 31 anxiety, 24 agitation/aggression, 23 apathy, 18 disinhibition, and 11 euphoria. Tests of attention and processing speed (PASAT), verbal fluency (COWAT), sorting (D-KEFS), and verbal learning and recall (CVLT-II) were not predictive of neuropsychiatric symptoms.

Perseveration and intrusions, as measured by the Stroop test and the CVLT-II, were highly predictive of neuropsychiatric symptoms.

Physicians should consider screening for neuropsychiatric symptoms in patients with MS, particularly in those with cognitive complaints, commented the researchers. They also advised that patients with MS who have impairment on the Stroop test or intrusions or repetitions on the CVLT-II be screened for neuropsychiatric symptoms.

CHICAGO—Many of the neuropsychologic tests that target cognitive domains affected in patients with multiple sclerosis (MS) do not appear to be predictive of neuropsychiatric symptoms in these patients, as has been previously hypothesized, reported Jesus Lovera, PhD, and colleagues. Neuropsychiatric symptoms occur in 80% of patients with MS, and depression is the most common of these symptoms, the researchers stated at the 60th Annual Meeting of the American Academy of Neurology.

The investigators studied 109 patients (mean age, 51) who were enrolled in clinical trials of memantine for cognitive impairment in MS. Among the inclusion criteria were significant cognitive complaints, a score 1 SD below the normal population average on the Paced Auditory Serial Addition Test (PASAT) or the California Verbal Learning Test-II (CVLT-II), and a Beck Depression Inventory–IA score of less than 19.

Neuropsychologic tests included a three-second version of the PASAT, the CVLT-II, the Symbol Digits Modalities Test, the Delis-Kaplan Executive Function System (D-KEFS) sorting test, the Controlled Oral Word Association Test (COWAT), and the Victoria version of the Stroop test. Neuropsychiatric symptoms were assessed using the Modified Neuropsychiatric Inventory.

According to Dr. Lovera, who is an Instructor in the Department of Neurology at Oregon Health and Science University in Portland, and colleagues, 55 patients had one or more neuropsychiatric symptoms: 42 had irritability, 31 anxiety, 24 agitation/aggression, 23 apathy, 18 disinhibition, and 11 euphoria. Tests of attention and processing speed (PASAT), verbal fluency (COWAT), sorting (D-KEFS), and verbal learning and recall (CVLT-II) were not predictive of neuropsychiatric symptoms.

Perseveration and intrusions, as measured by the Stroop test and the CVLT-II, were highly predictive of neuropsychiatric symptoms.

Physicians should consider screening for neuropsychiatric symptoms in patients with MS, particularly in those with cognitive complaints, commented the researchers. They also advised that patients with MS who have impairment on the Stroop test or intrusions or repetitions on the CVLT-II be screened for neuropsychiatric symptoms.