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Original Contribution |

Multiple Sclerosis After Infectious Mononucleosis FREE

Trine Rasmussen Nielsen, MD; Klaus Rostgaard, MSc; Nete Munk Nielsen, MSc, MD, PhD; Nils Koch-Henriksen, MD, DMSc; Sven Haahr, MD, DMSc; Per Soelberg Sørensen, MD, DMSc; Henrik Hjalgrim, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Epidemiology Research, Statens Serum Institut, Copenhagen (Drs T. R. Nielsen, N. M. Nielsen, and Hjalgrim and Mr Rostgaard), National Institute of Public Health and Department of Neurology, Aalborg Hospital, Aalborg, (Dr Koch-Henriksen), Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus (Dr Haahr), and Danish Multiple Sclerosis Research Centre, Department of Neurology, Copenhagen University Hospital, Copenhagen (Dr Sørensen), Denmark.


Arch Neurol. 2007;64(1):72-75. doi:10.1001/archneur.64.1.72.
Text Size: A A A
Published online

Background  Infectious mononucleosis caused by the Epstein-Barr virus has been associated with increased risk of multiple sclerosis. However, little is known about the characteristics of this association.

Objective  To assess the significance of sex, age at and time since infectious mononucleosis, and attained age to the risk of developing multiple sclerosis after infectious mononucleosis.

Design  Cohort study using persons tested serologically for infectious mononucleosis at Statens Serum Institut, the Danish Civil Registration System, the Danish National Hospital Discharge Register, and the Danish Multiple Sclerosis Registry.

Setting  Statens Serum Institut.

Patients  A cohort of 25 234 Danish patients with mononucleosis was followed up for the occurrence of multiple sclerosis beginning on April 1, 1968, or January 1 of the year after the diagnosis of mononucleosis or after a negative Paul-Bunnell test result, respectively, whichever came later and ending on the date of multiple sclerosis diagnosis, death, emigration, or December 31, 1996, whichever came first.

Main Outcome Measure  The ratio of observed to expected multiple sclerosis cases in the cohort (standardized incidence ratio).

Results  A total of 104 cases of multiple sclerosis were observed during 556 703 person-years of follow-up, corresponding to a standardized incidence ratio of 2.27 (95% confidence interval, 1.87-2.75). The risk of multiple sclerosis was persistently increased for more than 30 years after infectious mononucleosis and uniformly distributed across all investigated strata of sex and age. The relative risk of multiple sclerosis did not vary by presumed severity of infectious mononucleosis.

Conclusions  The risk of multiple sclerosis is increased in persons with prior infectious mononucleosis, regardless of sex, age, and time since infectious mononucleosis or severity of infection. The risk of multiple sclerosis may be increased soon after infectious mononucleosis and persists for at least 30 years after the infection.

Despite many years of intensive research, the causes of multiple sclerosis (MS) remain unknown. The prevailing view is that MS is an autoimmune disorder that results from various environmental factors acting in a genetically susceptible host.1 Different lines of evidence have implicated infection with the Epstein-Barr virus (EBV) in the development of MS. Investigations have shown that levels of certain EBV antibodies correlate with MS disease activity2,3 and are predictive of MS risk in apparently healthy individuals.46 Because more than 90% of healthy adults are infected with EBV, infection alone is clearly insufficient to cause MS. Age at primary infection and the host's immunological response may be modifiers of the EBV-associated risk of MS. Accordingly, infectious mononucleosis, usually caused by EBV infection in adolescence, has been associated with an increased risk of MS in small cohort studies and, less compellingly, in case-control studies.7 However, the association between mononucleosis and the risk of MS remains poorly characterized with respect to sex and age at and time since mononucleosis. Because such information is pertinent to understanding the association, we assessed the risk of MS in a cohort study of patients diagnosed as having mononucleosis.

PATIENTS AND REGISTERS

We established a cohort of persons tested serologically during the period 1940 to 1988 for EBV-related mononucleosis by the modified Paul-Bunnell reaction for heterophile antibodies at Statens Serum Institut in Denmark.8,9 Specifically, all individuals with positive test results (ie, Paul-Bunnell reaction positive at titers of 1/32) were considered to have EBV-related mononucleosis. We also enrolled a subset of those with negative test results (ie, Paul-Bunnell reaction negative at titers of 1/32) in the same period as a comparison group to assess access to testing.9 Using information on name, sex, and date of birth recorded for each individual, we linked the cohort with the Danish Civil Registration System to obtain the personal identification number, unique to all Danish citizens alive on April 1, 1968, and later, as well as the vital status for these individuals.10 Personal identification numbers were found for 81% of the records sought. Using the personal identification number as key, we linked the cohort to the Danish Multiple Sclerosis Registry11 to obtain information on MS occurring in the cohort.

To evaluate the impact of mononucleosis severity, we reasoned that hospitalized patients would represent the most ill subset of mononucleosis cases. We therefore constructed another mononucleosis cohort based on the Danish National Hospital Discharge Register, which contains information on all discharge diagnoses of patients admitted to Danish hospitals since 1977.12 The cohort comprised all individuals registered with a diagnosis of mononucleosis (International Classification of Diseases, Injuries and Causes of Death, Eighth Revision [1977-1993] code 075 and 10thRevision [1994-1996] code DB27) during the period 1977 to 1996. Using the personal identification number as key, we obtained information on vital status and MS diagnosis from the Danish Civil Registration System and the Danish Multiple Sclerosis Registry, respectively.

DATA ANALYSIS

Follow-up of the patients with mononucleosis began on April 1, 1968, or January 1 of the year after the diagnosis of mononucleosis or after a negative Paul-Bunnell test result, respectively, whichever came later and ended on the date of MS diagnosis, death, emigration, or the date December 31, 1996, whichever came first. For persons with more than 1 test result recorded, follow-up started January 1 of the year after the positive test result or the most recent negative test result. The standardized incidence ratio (SIR) of MS in the cohort was expressed as the ratio of observed to expected cases based on disease patterns in the whole population. The expected number of MS cases was estimated as the sum of age-, sex-, and period-specific population-based incidence rates of MS in Denmark available from the Danish Multiple Sclerosis Registry, multiplied by correspondingly stratified person-years at risk. We estimated SIRs for MS stratified by sex, age at and time since the Paul-Bunnell test, and attained age, calculating 95% confidence intervals (CIs) for the SIRs, assuming a Poisson distribution of the observed cases. The MS risks were also compared between the cohorts with positive and negative Paul-Bunnell test results by Poisson regression analyses.13

Diagnosis of MS was used as the end point. However, because of the possible passage of several years between onset and diagnosis of MS, we conducted a parallel series of analyses using debut of MS symptoms as the end point. In modeling the incidence rate of debut symptoms of MS, we corrected for delayed reporting of MS symptoms adapting the method described by Esbjerg et al.14 (Details on the calculation of variance and the CIs are available from us.) In all analyses, P<.05 was considered statistically significant.

A total of 104 cases of MS observed vs 45.91 expected in the cohort of individuals who had positive Paul-Bunnell test results corresponded to an SIR of 2.27 (95% CI, 1.87-2.75) (Table). The risk of MS among hospitalized patients with mononucleosis was also increased (SIR, 2.50; 95% CI, 1.65-3.80) based on 22 observed cases of MS. With 68 observed cases, the MS risk in the cohort of persons who had negative Paul-Bunnell test results was not statistically significantly different from the risk prevailing in the general population (SIR, 1.23; 95% CI, 0.97-1.56). Compared with the cohort with negative Paul-Bunnell test results, the risk of MS was increased in the cohort with positive Paul-Bunnell test results (relative risk [RR], 1.71; 95% CI, 1.23-2.36), adjusted for calendar period, sex, attained age, and age at Paul-Bunnell testing.

Table Graphic Jump LocationTable. SIRs (With 95% CIs) for Multiple Sclerosis in Persons With Positive and Negative Reactions on the Paul-Bunnell Test

The MS risk was increased in both men and women (Table). In the positive vs negative Paul-Bunnell test result cohort comparison, the RR of MS appeared somewhat higher for men (RR, 2.33; 95% CI, 1.42-3.81) than for women (RR, 1.41; 95% CI, 0.94-2.10), although this difference was not statistically significant (P for homogeneity = .12), adjusting for calendar period, sex, attained age, and time since the Paul-Bunnell test.

Elevated SIRs for MS were observed for all ages at mononucleosis, except those 30 years or older, whether MS diagnosis (Table) or MS debut was used as the end point (data not shown). The SIR for MS diagnosis appeared to be inversely correlated with age at mononucleosis (P for trend = .03) (Table), but this trend was not seen in analyses of MS debut symptoms (P for trend = .18). No evidence was found that prior mononucleosis was associated with the risk of MS with onset in any particular age interval whether MS diagnosis (Table) or MS debut was the end point (data not shown).

When MS diagnosis was used as the end point, increased risk appeared 10 years or more after mononucleosis occurred and remained increased for more than 3 decades (Table). When MS debut was used as the end point, risk was increased in every 5-year period from the mononucleosis diagnosis (data not shown).

We followed up more than 25 000 persons with mononucleosis for more than 550 000 person-years and observed a more than 2-fold increased risk of MS. Whereas the observed increased MS risk as such is consistent with previous studies,7 the magnitude of our study allowed us to characterize the association in detail. With the exception of 1 case-control study in women,15 such information has not been reported in previous studies or the studies were too small for stratified analyses to be statistically meaningful.

In the present study, mononucleosis was associated with an increased RR of MS in both men and women. This observation is consistent with findings previously presented in a small subset of the present cohort (16 observed MS cases).16 Thus, the mechanisms that govern the mononucleosis-MS association seem to act in both sexes.

A susceptibility window for exposure to an MS agent has been proposed.17 Primary EBV infection in childhood typically entails no or mild symptoms but in adolescence often manifests as infectious mononucleosis.18 Ambiguous results were obtained in analyses of MS risk by age at mononucleosis diagnosis. Using MS diagnosis as the end point, MS risk was inversely correlated with age at mononucleosis diagnosis, but when using MS debut as the end point, this was not observed. In contrast, an increasing risk with increasing age at mononucleosis diagnosis was observed in a small US-based comparison.15 Although alternative interpretations are possible, our data provided little support for a particular MS susceptibility age window for mononucleosis.

We also assessed MS risk by time since having had mononucleosis. When MS diagnosis was considered, the elevated MS risk became statistically significant only 10 years or more after a mononucleosis diagnosis. Using MS debut as the outcome, however, RR was homogeneous from the period less than 5 years after a mononucleosis diagnosis and onward. The interpretation of these findings is challenging because of the natural history of MS. Assuming that environmental factors are crucial to its development, the period from exposure to MS diagnosis would be expected to correspond to an incubation period. This could not be established on a relative scale in the present analyses but would be apparent in an absolute risk analytical approach. Notably, the elevated MS risk was observed continuously for more than 3 decades after the diagnosis of mononucleosis, which may indicate that mononucleosis changes the immunological status and confers a permanent excess in MS risk. In this regard, Sauce et al19 have recently shown that mononucleosis confers an apparently permanent immunological alteration in the host, the consequences of which remain to be established.

Other possible explanations for the uniform MS risk pattern across age, sex, and time since diagnosis of mononucleosis include the possibility that, rather than or in addition to the EBV infection itself, the increased MS risk after a mononucleosis diagnosis reflects shared risk factors related either to late timing of the primary EBV infection or to a possibly genetically determined immunological propensity to react with infectious mononucleosis on primary EBV infection. High social class and correlates hereof have previously been considered risk factors for both mononucleosis18 and MS.20 However, no association between social class and MS in Denmark was observed by Koch-Henriksen21 or Bager et al,22 the latter of whom found no evidence that MS risk varied by family structure in a cohort study of 1.9 million Danes. Analogously, one could postulate a common genetic predisposition to both mononucleosis and MS. Although an association between MS and certain HLA types (especially HLA-DR2) have been established,23 no such relationship has yet been observed for infectious mononucleosis.24

The population-based setting in addition to the size of the cohort, the long follow-up time, and the unbiased ascertainment of both exposure and outcome by means of high-quality registries are among the strengths of our study. Furthermore, all MS cases were ascertained in the Danish Multiple Sclerosis Registry. The registry was established in 1956 and has since collected information on Danish MS patients; it has an estimated completeness exceeding 90%.11 We also validated our findings for the cohort with positive Paul-Bunnell test results in a hospitalized mononucleosis cohort, a group likely to have severe mononucleosis. The MS risk estimates were similar between the cohorts, indicating that severity of symptoms did not affect risk much.

Evaluations of the sensitivity and specificity of the Paul-Bunnell test for heterophile antibodies have demonstrated relatively low sensitivity and high specificity.25,26 Importantly, however, the low sensitivity of the Paul-Bunnell test presumably renders our results for the cohort with positive Paul-Bunnell test results conservative when compared with a possibly overestimated risk for the cohort with negative Paul-Bunnell test results, and thus hardly can explain the observed association.

To summarize, we observed a more than 2-fold increased risk of MS after mononucleosis apparent for up to 30 years of observation and uniformly distributed across strata of age and sex. This absence of variation in MS risk may reflect a permanent change in immunological status, which confers an excess in MS risk, a hypothesis that needs to be explored further.

Correspondence: Trine Rasmussen Nielsen, MD, Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark (trn@ssi.dk).

Accepted for Publication: September 6, 2006.

Author Contributions:Study concept and design: T. R. Nielsen, Haahr, Sørensen, and Hjalgrim. Acquisition of data: T. R. Nielsen, N. M. Nielsen, Koch-Henriksen, and Hjalgrim. Analysis and interpretation of data: T. R. Nielsen, Rostgaard, Sørensen, and Hjalgrim. Drafting of the manuscript: T. R. Nielsen. Critical revision of the manuscript for important intellectual content: Rostgaard, N. M. Nielsen, Koch-Henriksen, Haahr, Sørensen, and Hjalgrim. Statistical analysis: Rostgaard, Koch-Henriksen, and Hjalgrim. Obtained funding: T. R. Nielsen and Hjalgrim. Study supervision: N. M. Nielsen, Haahr, Sørensen, and Hjalgrim.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the Danish Medical Research Council.

Martyn  CN McAlpin's Multiple Sclerosis: The Epidemiology of Multiple Sclerosis.  New York, NY: Churchill; 1991:3-40
Wandinger  KJabs  WSiekhaus  A  et al.  Association between clinical disease activity and Epstein-Barr virus reactivation in MS. Neurology 2000;55178- 184
PubMed Link to Article
Cepok  SZhou  DSrivastava  R  et al.  Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 2005;1151352- 1360
PubMed Link to Article
Ascherio  AMunger  KLLennette  ET  et al.  Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 2001;2863083- 3088
PubMed Link to Article
Levin  LIMunger  KLRubertone  MV  et al.  Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 2005;2932496- 2500
PubMed Link to Article
Sundstrom  PJuto  PWadell  G  et al.  An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study. Neurology 2004;622277- 2282
PubMed Link to Article
Thacker  ELMirzaei  FAscherio  A Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol 2006;59499- 503
PubMed Link to Article
Kristensen  M Studies on the sero-diagnosis of mononucleosis infectiosa. Acta Pathol Microbiol Scand 1938;15(suppl 37)399- 408
Hjalgrim  HAskling  JRostgaard  K  et al.  Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med 2003;3491324- 1332
PubMed Link to Article
Malig  C CRS: The Civil Registration System in Denmark.  Copenhagen, Denmark: CRS Office, Ministry of the Interior; 1995
Koch-Henriksen  N The Danish Multiple Sclerosis Registry: a 50-year follow-up. Mult Scler 1999;5293- 296
PubMed Link to Article
Andersen  TFMadsen  MJorgensen  JMellemkjoer  LOlsen  JH The Danish National Hospital Register: a valuable source of data for modern health sciences. Dan Med Bull 1999;46263- 268
PubMed
Clayton  DHills  M Statistical Methods in Epidemiology.  Oxford, England: Oxford University Press; 1993
Esbjerg  SKeiding  NKoch-Henriksen  N Reporting delay and corrected incidence of multiple sclerosis. Stat Med 1999;181691- 1706
PubMed Link to Article
Hernan  MAZhang  SMLipworth  LOlek  MJAscherio  A Multiple sclerosis and age at infection with common viruses. Epidemiology 2001;12301- 306
PubMed Link to Article
Haahr  SKoch-Henriksen  NMoller-Larsen  AEriksen  LSAndersen  HM Increased risk of multiple sclerosis after late Epstein-Barr virus infection: a historical prospective study. Mult Scler 1995;173- 77
PubMed
Kurtzke  JFHyllested  K MS epidemiology in Faroe Islands. Riv Neurol 1987;5777- 87
PubMed
Evans  ASKaslow  RA Epidemiology and Control: Viral Infections of Humans. 4th ed. New York, NY: Plenum Medical Book Co; 1997
Sauce  DLarsen  MCurnow  SJ  et al.  EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15. Blood 2006;10811- 18
PubMed Link to Article
Wallin  MTPage  WFKurtzke  JF Epidemiology of multiple sclerosis in US veterans, VIII: long-term survival after onset of multiple sclerosis. Brain 2000;1231677- 1687
PubMed Link to Article
Koch-Henriksen  N An epidemiological study of multiple sclerosis: familial aggregation, social determinants, and exogenic factors. Acta Neurol Scand Suppl 1989;1241- 123
PubMed
Bager  PNielsen  NMBihrmann  K  et al.  Childhood infections and risk of multiple sclerosis. Brain 2004;1272491- 2497
PubMed Link to Article
Jersild  CFog  THansen  GSThomsen  MSvejgaard  ADupont  B Histocompatibility determinants in multiple sclerosis, with special reference to clinical course. Lancet 1973;21221- 1225
PubMed Link to Article
Ythier  AMoreau  JFPeyrat  MABignon  JDSoulillou  JP HLA-AB and -DR types in patients with infectious mononucleosis (IM). Tissue Antigens 1983;21329- 332
PubMed Link to Article
Evans  ASNiederman  JCCenabre  LCWest  BRichards  VA A prospective evaluation of heterophile and Epstein-Barr virus-specific IgM antibody tests in clinical and subclinical infectious mononucleosis: specificity and sensitivity of the tests and persistence of antibody. J Infect Dis 1975;132546- 554
PubMed Link to Article
Bruu  ALHjetland  RHolter  E  et al.  Evaluation of 12 commercial tests for detection of Epstein-Barr virus-specific and heterophile antibodies. Clin Diagn Lab Immunol 2000;7451- 456
PubMed

Figures

Tables

Table Graphic Jump LocationTable. SIRs (With 95% CIs) for Multiple Sclerosis in Persons With Positive and Negative Reactions on the Paul-Bunnell Test

References

Martyn  CN McAlpin's Multiple Sclerosis: The Epidemiology of Multiple Sclerosis.  New York, NY: Churchill; 1991:3-40
Wandinger  KJabs  WSiekhaus  A  et al.  Association between clinical disease activity and Epstein-Barr virus reactivation in MS. Neurology 2000;55178- 184
PubMed Link to Article
Cepok  SZhou  DSrivastava  R  et al.  Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 2005;1151352- 1360
PubMed Link to Article
Ascherio  AMunger  KLLennette  ET  et al.  Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 2001;2863083- 3088
PubMed Link to Article
Levin  LIMunger  KLRubertone  MV  et al.  Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 2005;2932496- 2500
PubMed Link to Article
Sundstrom  PJuto  PWadell  G  et al.  An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study. Neurology 2004;622277- 2282
PubMed Link to Article
Thacker  ELMirzaei  FAscherio  A Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol 2006;59499- 503
PubMed Link to Article
Kristensen  M Studies on the sero-diagnosis of mononucleosis infectiosa. Acta Pathol Microbiol Scand 1938;15(suppl 37)399- 408
Hjalgrim  HAskling  JRostgaard  K  et al.  Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med 2003;3491324- 1332
PubMed Link to Article
Malig  C CRS: The Civil Registration System in Denmark.  Copenhagen, Denmark: CRS Office, Ministry of the Interior; 1995
Koch-Henriksen  N The Danish Multiple Sclerosis Registry: a 50-year follow-up. Mult Scler 1999;5293- 296
PubMed Link to Article
Andersen  TFMadsen  MJorgensen  JMellemkjoer  LOlsen  JH The Danish National Hospital Register: a valuable source of data for modern health sciences. Dan Med Bull 1999;46263- 268
PubMed
Clayton  DHills  M Statistical Methods in Epidemiology.  Oxford, England: Oxford University Press; 1993
Esbjerg  SKeiding  NKoch-Henriksen  N Reporting delay and corrected incidence of multiple sclerosis. Stat Med 1999;181691- 1706
PubMed Link to Article
Hernan  MAZhang  SMLipworth  LOlek  MJAscherio  A Multiple sclerosis and age at infection with common viruses. Epidemiology 2001;12301- 306
PubMed Link to Article
Haahr  SKoch-Henriksen  NMoller-Larsen  AEriksen  LSAndersen  HM Increased risk of multiple sclerosis after late Epstein-Barr virus infection: a historical prospective study. Mult Scler 1995;173- 77
PubMed
Kurtzke  JFHyllested  K MS epidemiology in Faroe Islands. Riv Neurol 1987;5777- 87
PubMed
Evans  ASKaslow  RA Epidemiology and Control: Viral Infections of Humans. 4th ed. New York, NY: Plenum Medical Book Co; 1997
Sauce  DLarsen  MCurnow  SJ  et al.  EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15. Blood 2006;10811- 18
PubMed Link to Article
Wallin  MTPage  WFKurtzke  JF Epidemiology of multiple sclerosis in US veterans, VIII: long-term survival after onset of multiple sclerosis. Brain 2000;1231677- 1687
PubMed Link to Article
Koch-Henriksen  N An epidemiological study of multiple sclerosis: familial aggregation, social determinants, and exogenic factors. Acta Neurol Scand Suppl 1989;1241- 123
PubMed
Bager  PNielsen  NMBihrmann  K  et al.  Childhood infections and risk of multiple sclerosis. Brain 2004;1272491- 2497
PubMed Link to Article
Jersild  CFog  THansen  GSThomsen  MSvejgaard  ADupont  B Histocompatibility determinants in multiple sclerosis, with special reference to clinical course. Lancet 1973;21221- 1225
PubMed Link to Article
Ythier  AMoreau  JFPeyrat  MABignon  JDSoulillou  JP HLA-AB and -DR types in patients with infectious mononucleosis (IM). Tissue Antigens 1983;21329- 332
PubMed Link to Article
Evans  ASNiederman  JCCenabre  LCWest  BRichards  VA A prospective evaluation of heterophile and Epstein-Barr virus-specific IgM antibody tests in clinical and subclinical infectious mononucleosis: specificity and sensitivity of the tests and persistence of antibody. J Infect Dis 1975;132546- 554
PubMed Link to Article
Bruu  ALHjetland  RHolter  E  et al.  Evaluation of 12 commercial tests for detection of Epstein-Barr virus-specific and heterophile antibodies. Clin Diagn Lab Immunol 2000;7451- 456
PubMed

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