Uncertain Role of Herpesvirus Infection in Multiple Sclerosis
abstracts & commentary
Sources: Ablashi DV, et al. Human Herpesvirus-6 (HHV-6) infection in multiple sclerosis: A preliminary report. Multiple Sclerosis 1998;4:490-496; Dockrell DH, et al. Human Herpesvirus 6. Mayo Clin Proc 1999;74:163-170; Ross RT, et al. Herpes zoster and multiple sclerosis. Can J Neurol Sci 1999;26:29-32.
National media attention has recently been drawn to the possible role of human herpesvirus-6 (HHV-6) in multiple sclerosis (MS), and consequently, neurologists have been barraged by anxious patient inquiries about being tested and treated for "the virus that causes MS." In fact, several reports over the past four years have sought to strengthen the relationship of HHV-6 in MS. (See Neurol Alert 1996;14:51-52; Neurol Alert 1997;16:14; Infect Dis Alert 1998;17:65-66.)
In a small study presented at the recent ANA meeting (Knox K, et al. Ann Neurol 1998;44:485A), three of eight MS patients showed evidence of active HHV-6 in the blood, and active HHV-6 could be found in the brain (7 of 10) or lymphoid (6 of 9) tissues of MS patients, but rarely in controls. Other reports by Ablashi and associates (and previously by Soldan SS, et al. Nat Med 1997;3:1394-1397) have suggested an increased incidence of IgG and IgM antibodies against certain HHV-6 antigens in the CSF and serum of MS patients compared to controls. Similarly, HHV-6 was more likely to be detected by PCR DNA amplification or isolated by culture in the blood or CSF of MS patients. Not all investigators, however, have found a correlation of HHV-6 with MS, in that in some studies the virus was detected as commonly in controls as in MS patients (e.g., Mayne M, et al. Ann Neurol 1998;44:391-394).
A review of HHV-6 by Dockrell and associates provides a perspective on the clinical biology and epidemiology of this ubiquitous virus. As with other human herpes viruses, (e.g., varicella zoster [VZV], Epstein-Barr virus [EBV], and cytomegalovirus [CMV]), HHV-6 is a common virus, with most patients being infected early in childhood. Occasionally the primary infection is manifest as fever and an erythematous rash (roseola infantum). Thus, virtually all persons with or without MS are infected and will have a "positive" HHV-6 IgG serology and, often, latent virus detectable by sensitive PCR methodology. A causal relationship of HHV-6 with MS may be difficult to make, and hinges on the distinction that MS patients are more likely to have reactivated virus in their blood or central nervous system.
Many clinicians have described in the literature that a variety of human herpesvirus infections such as HSV, EBV, and CMV can trigger inflammatory, demyelinating events in patients (e.g., see Apatoff BR. Neurol Infect Epidemiol 1997;2:99-102). Ross and associates studied the epidemiology of herpes zoster (HZ, caused by VZV, or HHV-3) in 633 Canadian MS patients, in which there was a 16.8% positivity rate of HZ, compared to 5.4-6.8% of control groups. HZ occurred at an earlier age in the MS group, with the majority of male patients having HZ prior to a diagnosis of MS. This history of HZ preceding MS is important, as corticosteroids or other immunosuppressive therapy could increase the HZ in the MS population.
COMMENTARY
Thus, the potential role of HHV-6 as a specific cofactor in MS needs to be further defined. HHV-6 may be one of a variety of persistent herpesvirus infections contributing to the pathogenesis of the disease, either by direct cytopathic effects of virus, or by activation of the immune system, which targets both the virus and secondarily the central nervous system. It is possible that the benefit of interferon-beta therapy in controlling MS disease activity may be by an antiviral effect. However, there is no convincing evidence that antiviral drugs against HHV-6 are an effective treatment for MS. Those drugs, ganciclovir and foscarnet, have considerable toxicity, require IV administration, and will require careful testing in controlled studies to determine safety and efficacy. One pilot study for MS patients with severe refractory disease is currently under way at New York Hospital-Cornell Medical Center. HHV-6 is relatively resistant to acyclovir and the related oral antivirals valacyclovir and famcyclovir, and their casual use as a treatment for MS cannot be supported at this time. A controlled trial of valacyclovir in relapsing MS is now being conducted at Rockefeller University by Drs. John Zabriske and Jacqueline Friedman.
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