Risk Factors for MS in Children—Do Environmental Conditions Have a Causal Role?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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