From the 1Department of Neurology, and
2Departments of Epidemiology, Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, AL.
Address correspondence to: Richard A. Kaslow, Departments of Epidemiology, Medicine and Microbiology, University of Alabama at Birmingham, 220A Ryals Building, 1665 University Blvd, Birmingham, AL 35294-0022; firstname.lastname@example.org.
Multiple sclerosis (MS) is a debilitating and frequently progressive neurologic disease that usually strikes before the age of 50. The pathophysiology involves an immune-mediated demyelination of the central nervous system (CNS) white matter. Although the cause of MS remains unknown, both genetic and environmental factors seem quite likely to be operating long before the initial clinical presentation (perhaps even many years before).
Several lines of evidence support the involvement of an exogenous (possibly infectious) agent. There are geographic differences in risk within the same ethnic groups, as well as variations in incidence over time. Furthermore, viruses have been known to produce demyelination in animals (eg, canine distemper), and in humans (eg, postinfectious encephalomyelitis). A major line of inquiry has involved comparative measurements of antibodies to various infectious agents in the blood, cerebrospinal fluid (CSF) or CNS tissue of MS patients 1 (Table 1). For most of these hypothesized agents, evidence of association with MS has been unconvincing.
Chlamydia pneumoniae has been getting increased attention as a possible cause of MS. Since the initial report 2 20 years ago suggesting an association between C. pneumoniae and MS, this hypothesis has been explored in numerous studies, including one in this issue of Epidemiology. 3C. pneumoniae is a common respiratory pathogen, with up to 70% of the adult population carrying antibodies against this organism. 4 Using a sensitive PCR technique, Sriram et al. 5 reported that a remarkable 97% of the CSF samples from MS patients were positive for C. pneumoniae, compared with only 18% of the samples from controls. These authors also isolated the organism from CSF of 64% of MS patients compared with11% of patients with other neurologic diseases. Although some studies have supported these observations, 6–10 many others have not. 11–21 What might account for these inconsistencies?
There are formidable technical difficulties in the diagnosis of C. pneumonia infection. The agent is not easily cultivated in the laboratory, and its detection has relied heavily on indirect methods, especially polymerase chain reaction (PCR). Depending on the assay used, there can be problems with both sensitivity and specificity. Other difficulties with previous studies include small sample size and selection of inadequate controls. In addition, the process of MS may itself unmask or reactivate a long-dormant and harmless infectious agent. However, one of the biggest obstacles has been the dependence on cross-sectional study designs.
“. . .the process of MS may itself unmask or reactivate a long-dormant and harmless infectious agent.”
In this issue of Epidemiology, Ascherio and colleagues 3 explore this question in the Nurses Health Studies. The authors use a nested case-control design, matching controls to cases by age. This study overcomes certain problems in previous work (such as small sample size, use of nonstandardized or insensitive measures for detecting infection, lack of proper blinding, inadequate control population and exclusion of certain MS clinical subtypes). However, inferences from this analysis are still limited by the fact that nearly all blood samples were collected after the onset of disease. The inability to establish the temporal relation between onset of infection and development of MS leaves open the possibility of aberrant immune response attributable to MS itself, or possible immunomodulatory treatment effects on serological assays or on reactivation of latent infection.
The conflicting literature on C. pneumoniae and MS underscores the substantial difficulties inherent in studying the cause of a multifactorial, heterogeneous chronic disease, where the underlying pathogenetic process is likely to be initiated years, and possibly decades, before the first clinical manifestations. Although it is plausible that C. pneumoniae may be a cause of MS, such a relation is far from conclusive. More definitive efforts might include a longitudinal follow-up in children infected with C. pneumoniae, or documentation of transmission of MS with chlamydia among humans or from humans to animals. Another approach currently under way involves a randomized clinical trial of antibiotics directed against C. pneumoniae in well-defined MS patient populations. Of course, a trial that targets a microbe whose direct damage may have been inflicted long before symptoms occurred may produce a false negative result.
In any case, further cross-sectional studies based on serology are unlikely to shed additional light. Well-designed, intensive epidemiologic and clinical investigations will be needed to produce more direct and compelling evidence for the role of infection. For now it remains unclear whether C. pneumoniae will emerge as a true causal factor or will join the long list of discarded candidate etiologic agents of MS.
About the Authors
KHURRAM BASHIR , an Assistant Professor of Neurology at the University of Alabama at Birmingham, focuses on neuroimmunologic disorders including multiple sclerosis. He directs the multiple sclerosis clinic at the Birmingham Veterans Medical Center where he is engaged in clinical and epidemiologic studies.
RICHARD KASLOW is Professor of Epidemiology, Medicine and Microbiology at the University of Alabama at Birmingham. He leads the Program in Epidemiology of Infection and Immunity. With long-standing interest in the immune response to infectious agents, he has studied the potential transmissibility of multiple sclerosis. More recently, his work has concentrated on host genetic factors that influence HIV and other infections.
1. Bashir K, Whitaker JN. Handbook of Multiple Sclerosis
. Philadelphia, Lippincott Williams & Wilkins, 2001;191–207.
2. Perlmutter LJ, Darvish M. Possible relationship of chlamydia to multiple sclerosis. Med Hypotheses 1983; 12: 95–98.
3. Munger LK, Peeling RW, Hernán MA, et al
. Infection with Chlamydia pneumoniae
and risk of multiple sclerosis. Epidemiology 2003; 14: 141–147.
4. Gaydos CA. Chlamydia pneumoniae
and its proposed link to multiple sclerosis: to be or not to be? Neurology 2001; 56: 1126–1127.
5. Sriram S, Stratton CW, Yao S, et al
. Chlamydia pneumoniae
infection of the central nervous system in multiple sclerosis. Ann Neurol 1999; 46: 6–14.
6. Yao S-Y, Stratton CW, Mitchell WM, Sriram S. CSF oligoclonal bands in MS include antibodies against Chlamydophila
antigen. Neurology 2001; 56: 1168–1176.
7. Layh-Schmitt G, Bendl C, Hildt U, et al
. Evidence for infection within a subgroup of patients with multiple sclerosis. Ann Neurol 2000; 47: 652–655.
8. Krametter D, Niederwieser G, Berghold A, et al
. Chlamydia pneumoniae
in multiple sclerosis: humoral immune responses in serum and cerebrospinal fluid and correlation with disease activity marker. Mult Scler 2001; 7: 13–18.
9. Pincherle A, Blasi F, Filippi M, et al
. Association between Chlamydia pneumoniae
infection and clinical activity in multiple sclerosis. Neurology 2001; 56: A450.
10. Gorham K, Peeling R, Hernan M, et al
. Chlamydia pneumoniae
serology and risk of multiple sclerosis. Neurology 2001; 56: A451.
11. Hammerschlag MR, Ke Z, Lu F, Roblin J, Boman G, Kalman B. Chlamydia pneumoniae
present in brain lesions of patients with multiple sclerosis? J Clin Microbiol 2000; 38: 4274–4276.
12. Ke Z, Lu F, Roblin J, Boman G, Hammerschlag MR, Kalman B. Lack of detectable Chlamydia pneumoniae
in brain lesions of patients with multiple sclerosis. Ann Neurol 2000; 48: 400.
13. Morre SA, De Groot CJ, Killlestein J, et al
. Is Chlamydia pneumoniae
present in the central nervous system of multiple sclerosis patients? Ann Neurol 2000; 48: 399.
14. Zuzak KB, Theodore M, Kaufman M, et al
. Lack of detection of by PCR and tissue cultures in cerebrospinal fluids from multiple sclerosis patients and controls. In: Saikku P, ed. Proceedings of the 4th Meeting of the European Society for Chlamydia Research
. Bologna, Italy: Societa Edtrice Esculapio, 2000:303.
15. Pucci E, Taus C, Cartechini E, et al
. Lack of Chlamydia
infection of the central nervous system in multiple sclerosis. Ann Neurol 2000; 48: 399–400.
16. Poland SD, Rice GPA. Chlamydia pneumoniae
and multiple sclerosis. Neurology 2000; 54: A165.
17. Li WP, Ming X, Cook SD, Blumberg B, Dowling P. Chlamydia pneumoniae
sequence frequently present in both MS and control spinal fluid. Neurology 2000; 54: A165.
18. Derfuss T, Guerkov R, Bergh F, et al
. Intrathecal immune response against Chlamydia pneumoniae
in multiple sclerosis. Neurology 2001; 56: A451–A452.
19. Derfuss T, Guerkov R, Bergh F, et al
. Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response. Brain 2001; 124: 1325–1335.
20. Sotgiu S, Piana A, Pugliatti M, et al
. Chlamydia pneumoniae
in the cerebraspinal fluid of patients with multiple sclerosis and neurological controls. Mult Scler 2001; 7: 372–374.
21. Gieffers J, Pohl D, Treib J, et al
. Presence of Chlamydia pneumoniae
DNA in the cerebral spinal fluid is a common phenomenon in a variety of neurological diseases and not restricted to multiple sclerosis. Ann Neurol 2001; 49: 585–589.