Expert Consultant
Andrew D. Goodman, MD, Department of Neurology, University of Rochester Medical Center, Rochester, NY

Progress to Date

Since multiple sclerosis (MS) lesions seem to be caused by immune attacks, one likely explanation for MS is that it is an autoimmune disease; that is, a disease in which the immune system incorrectly identifies one of the body’s normal components as foreign and attacks it. Another possibility is that MS is triggered by an infectious agent––like a virus or bacteria that has infected the nervous system.

There are several ways that an infectious agent might contribute to MS. For example, viruses or bacteria might directly damage the central nervous system (CNS) tissue during the course of the infection. Alternatively, the damage may result from the body’s immune response to the infection, which causes inflammation. If the infectious agent were a virus that had periods of dormancy and periods of reactivation, viral reactivation could lead to repeated immune attacks. Finally, an infectious agent might trigger an autoimmune response if the immune system was tricked by the infection into mistakenly attacking the nervous system. This situation, which could occur if, say, a viral protein was very similar to a human protein, is called “molecular mimicry. ”

Evidence from several sources hints that an infectious agent might be involved in MS (Jacobson & Cross, 2001). For example, some apparent clusters of MS cases have been reported, which is consistent with infection or some other environmental trigger. MS is more frequent at higher latitudes, also consistent with a trigger in the environment. People who contract “childhood” diseases at later ages may run an increased risk of MS, implicating infection. Certain viral infections can cause destruction of myelin and a relapsing-remitting pattern of attacks in experimental animals. Finally, patients with MS make more antibodies to certain infectious agents than do people without MS.

Although these pieces of evidence taken together suggest a role for an infectious agent in MS, no such agent has been definitively identified. In fact, over the years, several possible viruses have been proposed as candidate triggers for MS, but none has stood up under close scrutiny. Since the course of MS is so variable, there is growing enthusiasm for the idea that MS results from different triggers in different patients, with viruses or bacteria playing a role in some cases, but perhaps not all.

Current Research

Human Herpesvirus-6: Many people are familiar with the human herpesvirus family. These are the viruses that bring us cold sores and chicken pox. One member of this family is human herpesvirus-6 (HHV-6), a virus that has been associated with certain CNS infections, like meningitis and encephalitis, in people with impaired immune systems (Meinl, 2002). Although apparently dangerous to some people whose immune system has been compromised, 90% of children younger than 3 years are infected with HHV-6 with few ill effects besides fever or rash (roseola). After this first infection, the virus becomes “latent.” That is, it does not replicate itself and makes only a few viral proteins. The virus can reactivate and replicate, but the process of reactivation and the factors that trigger it are not well understood. Reactivation can often be detected, however, because an antibody to HHV-6 frequently can be found in the blood during reactivation (Meinl, 2002).

A potential role for HHV-6 in MS was suggested by Challoner et al. (1995), who found that DNA from HHV-6 was present at higher levels in brain tissue from patients with MS than from control subjects. Looking at the DNA amounts was important because some level of HHV-6 DNA was found in 78% of MS brains and 74% of control brains. (This is not a significant difference, and shows only that most people have a latent HHV-6 brain infection.) The researchers went on to stain brain specimens for HHV- 6 proteins, using antibodies. They found a difference in the way cells called oligodendrocytes were stained in MS and control brains. Oligodendrocytes are the cells that make the myelin sheaths that are destroyed by MS. In the brains of those with MS, the antibodies often stained oligodendrocytes, especially oligodendrocytes that w e re associated with lesions. In some cases, clusters of oligodendrocytes that were faraway from lesions were stained, leading the authors to wonder if viral infection in oligodendrocytes might occur before the lesions formed. The authors did not see stained oligodendrocytes in control brains, even when the subjects had other neurological disorders like Parkinson’s or Alzheimer’s disease.

Since Challoner et al.’s paper was published, several other groups have tried to find evidence of HHV-6 infection or reactivation in MS with variable success (reviewed by Meinl, 2002). HHV-6 has been found in MS lesions by some groups and not by others. In a small study, antibodies to the virus were found in about two thirds of a group of patients with relapsing-remitting MS, but in only one fifth of controls. Future studies will be required to determine the actual role of HHV-6, if any, in MS.

Epstein-Barr Virus: Epstein-Barr virus (EBV) is another member of the herpesvirus family and is well known for causing infectious mononucleosis. Almost all people are infected by EBV at some point in their lives and carry a latent infection. EBV has been under suspicion for involvement in MS for some time. In a recent paper, Wandinger et al. (2000) investigated whether latent EBV infections became reactivated in patients with MS, and found that more than 70% of 19 patients who had relapses during the period of the study also had reactivations of EBV during this time. None of the patients with stable disease had an EBV reactivation. This is a very small number of patients, but the results are intriguing and are consistent with the idea that EBV might be involved in some way with MS relapses.

Bacteria: Viruses are not the only potential infectious agent involved in MS. Chlamydophila pneumoniae, a type of bacteria, is another recent candidate to be nominated for such a role (Yao, Stratton, Mitchell, & Sriram, 2001). These bacteria can cause chronic diseases affecting the CNS as well as other organs. The same group of researchers found evidence that the CNS of several patients with MS was infected with the bacteria C. pneumoniae. One characteristic of MS is the presence of abnormal antibodies in the cerebrospinal fluid (CSF). There has been some speculation that these antibodies are the body’s response to an infectious agent that causes MS, and that identifying the agent that provokes the body to make the antibodies might lead to finding the cause of the disease (Jacobson & Cross , 2001). Yao et al. (2001) showed that antibodies in the CSF of 14 of 17 patients with MS recognized C. pneumoniae. Patients with other neurological diseases did not have antibodies that reacted with C . pneumoniae. The authors of the study believe their findings support a link between chronic infection with C. pneumoniae and MS. However, other laboratories have not been able to confirm these findings. While this study has garnered considerable interest(see Gaydos, 2001; Jacobson & Cross, 2001), the current consensus is that further investigation is required.

Vaccinations: A separate issue from the issue of how infectious agents might influence MS is the effect vaccinations may have on the course of MS. Since vaccinations trigger an immune response, there has been some concern that the resulting immune reaction might lead to MS or trigger a relapse. After a mass immunization campaign in France for hepatitis B, several MS cases developed. Therefore, Ascherio et al. (2001) investigated the association between vaccination and the occurrence of new cases of MS in more than 800 nurses and found no correlation. This vaccine has now been cleared of suspicion.

In a different study, Confavreux et al. (2001) investigated whether there was an increased risk of relapse among more than 600 patients with MS who had had any kind of vaccination. They found that vaccinations against tetanus, hepatitis B, and influenza were not associated with an increased risk of relapse, and that there was a slightly smaller risk of relapse with most common vaccinations, including diphtheria, polio, and tetanus. These two studies suggest that routine vaccination is safe for people with MS.

Future Research

The idea of an infectious agent playing an important role in MS is attractive, not least because new drugs could be identified to target such an agent. However, a recent clinical trial of the antiherpes drug valacyclovir did not lead to improvement in the number of new lesions or relapses experienced by patients with MS (reviewed by Goodman & Miller, 2002). Although it may be too early to dismiss herpesviruses as important in MS on the basis of this one result, it is consistent with other trials of antiviral therapies in MS (Goodman & Miller, 2002). Nevertheless, more trials of this type are expected in the future.

Implications for People With MS

While investigators will continue their research into the role of infection and infectious agents in MS, currently available information is not strong enough to suggest changes in patient care. Clinicians can, however, encourage their patients to enroll, as appropriate, in studies that will promote a clearer understanding of this issue. There has been some reluctance to vaccinate patients with MS because of concern that vaccinations might precipitate a relapse. Current research indicates that vaccinations are safe and should not be withheld from patients with MS (Confavreux et al., 2001).

References (*- denotes suggested readings)

Ascheiro, A., Zhang, S., Hernan , M. A., Olek, M. J., Coplan, P. M., & Brodovicz, K. (2001). Hepatitis B vaccination and the risk of multiple sclerosis. New England Journal of Medicine, 344 , 327 - 332 .

Challoner, P. B., Smith, K. T., Parker, J. D., MacLeod, D. L., Coulter, S. N., Rose, T. M., et al. (1995). Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proceedings of the National Academy of Science, 92, 7440 - 7444 .

Confavreux, C., Suissa, S., Saddier, P., Bourdes, V., Vukusic, S., & The Vaccines in Multiple Sclerosis Group. (2001). Vaccinations and the risk of relapse in multiple sclerosis. New England Journal of Medicine, 344, 319 - 326 .

*Gaydos, C. A. (2001). Chlamydia pneumonidae and its proposed link to multiple sclerosis: To be or not to be? Neurology, 56, 1126-1127.

Goodman, A. D., & Miller, D. H. (2002). Infections and MS. Clinical trials move to center stage. Neurology, 58, 7-8.

*Jacobson, S., & Cross, A. (2001). Association of Chlamydia pneumoniae and multiple sclerosis. Stage two? Neurology, 56, 1128-1129.

*Meinl, E. (1999). Concepts of viral pathogenesis of multiple sclerosis. Current Opinion in Neurology, 12, 303-307.

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