[Sem Neurology 20(3):375-386, 2000. © 2000 Thieme Medical Publishers, Inc.]
Since its initial description by Charcot more than 100 years ago, multiple sclerosis (MS) has been suspected of being related to infection. In the past few years, investigators have identified two newer agents, Chlamydia pneumoniae and HHV-6, in patients with MS. The studies concerning both agents have been of great interest, but controversy nonetheless surrounds the relationship of either agent to demyelinating disease.
In 1998, Sriram et al reported a patient with progressive MS whose condition continued to decline despite multiple courses of immunosuppressive treatment. The patient's serum and CSF contained antibodies specific for C. pneumoniae, and the presence of C. pneumoniae in CSF was confirmed by both PCR and culture. Following antibiotic treatment directed at C. pneumoniae, the patient improved dramatically from a pretreatment expanded disability status scale (EDSS) score of 7.0 to 3.0 after treatment. The case not only suggested that a common pathogen might be identified in MS but also raised the hope that MS might be treated successfully with antibiotic therapy. Sriram et al. have subsequently gone on to show that C. pneumoniae can be detected by PCR and/or culture in a high percentage of their MS patients, especially those with chronic progressive disease. Most interestingly, they further demonstrated that oligoclonal immunoglobulins in MS CSF may bind C. pneumoniae antigens, whereas immunoglobulins in the CSF of patients with other inflammatory diseases of the CNS failed to do so. In these studies, however, normal CSF from occasional patients was positive for C. pneumoniae by PCR or culture.
Other investigators have been much less successful in demonstrating C. pneumoniae DNA or infectious organisms in CSF from patients with MS. To date C. pneumoniae has not been detected in CNS tissue from MS patients using techniques such as immunohisto-chemistry or in situ hybridization, nor has the organism been cultured directly from brain as opposed to CSF. Although cellular immune response is known to be of great importance in the pathogenesis of MS, cellular immune response to C. pneumoniae organisms has not been stud-ied in MS patients.
The role of C. pneumoniae infection in MS is therefore yet to be defined, and the contribution of the organism to the pathogenesis of MS remains to be fully elucidated. The organism potentially could be etiologic in some patients with MS.[124-130] A role for the organism in the pathogenesis of MS would be likely if antigens from this organism were found to absorb, specifically, oligoclonal bands from the CSF of large numbers of MS patients, because data of this sort would be comparable to those found in other CNS infections in which pathogen-specific oligoclonal CSF immunoglobulins are present. Isolation of the organism from MS lesions would be another major step in confirming a role for this pathogen. However, it is equally possible that C. pneumoniae, even if frequently detected, may not be a causative agent in MS but rather, like other infectious agents, may influence the course of MS indirectly by potentiating the dis-ease. In this scenario, the organism could nonspecifically stimulate the immune system, resulting in relapse or progression of disease. Alternatively, C. pneumoniae could activate macrophages directly or damage cerebral endothelial cells and add to ongoing damage at sites of demyelination.
Finally, it remains possible despite promising early evidence that C. pneumoniae is not important in the initiation and evolution of MS for the majority of patients.
Careful attention to the details of specimen handling, PCR, and culture techniques will be required to determine whether there is a significant role for C. pneumoniae in MS. Until more evidence is provided, antibiotic treatment for MS should be reserved for patients in well-designed clinical trials.
Human Herpesvirus 6
HHV-6 is a neurotropic virus that can be detected in normal brain and in the brains of patients with MS. The virus is known to produce encephalitis in the setting of impaired host immunity, including patients with HIV infection and organ transplantation. The virus may infect both oligodendrocytes and microglia in culture and peripheral blood mononuclear cells (PBMCs) in vivo.[133,134] A receptor for the virus, CD46, has been identified. The virus may potentially be highly pathogenic when in the presence of coinfecting viruses such as CMV or HIV. The virus genome has been demonstrated to integrate into the human genome on chromosome 17, giving it the potential to persist despite intact host immune response. Sola et al, using PCR methodology, reported detection of HHV-6 DNA in PBMCs from an MS patient in 1993. Since then, many studies have evaluated serum and CSF antibody titers for HHV-6 and PCR of PBMCs and CSF; these studies have produced widely varying results.[138-149] An important study by Challoner et al, using molecular virological techniques, demonstrated viral nucleic acid of HHV-6B in both MS and normal brains, suggesting that the virus may be resident in the human CNS. Immunohistochemical techniques demonstrated a preponderance of virus-specific staining around demyelinating lesions, with much less staining in the normal-appearing white matter of the MS brains. Further, the virus frequently appeared to be associated with oligodendrocytes. Subsequently, Sanders et al, in PCR studies of MS brain tissue, reported a greater association of HHV-6 with active than inactive plaques. It should be noted that these investigators also detected other herpesviruses including herpes simplex virus and varicellazoster virus. It has been demonstrated that HHV-6 may be detected around areas of demyelination in other diseases in addition to MS, including PML.
There are intriguing case reports of fulminant demyelinating disease and encephalitis in MS patients in which HHV-6 has been clearly identified as a pathogen.[153-155] These cases suggest that the virus may have a role in some cases of MS or could be a complicating factor potentiating MS. Overall, the evidence at present is inconsistent and it is unlikely that HHV-6 is a primary pathogen in the majority of patients. It is also possible that HHV-6 is the primary pathogen in some of the cases of MS, whereas in others it may facilitate disease progression. Further investigations of HHV-6 in large patient populations -- in particular at onset of the disease prior to any immune therapy -- may help to define the role of the virus in MS. Standardization of immunological and PCR techniques will be most useful in accurately determining immunoglobulin titers and presence of viral DNA. Detection of viral DNA in acellular CSF is very important in future studies to ensure that the nucleic acid was not due to the presence of infected cells that migrated from peripheral blood.[156,157]
Although HHV-6 is a herpesvirus and potentially susceptible to antiviral therapy, it would be premature to advocate the general use of these medications for MS patients. These are best restricted to clinical trials. If treatment is to be initiated, it will be important to determine the subclass of the virus because HHV-6B is less sensitive to some antiviral agents than HHV-6A.
The history of research into the etiology of MS has been one of putative causative agents reported in haste and disproved over time,[158,159] and it remains to be determined whether C. pneumoniae and HHV-6 are primary pathogens in MS. Several points are of great importance in assessing the role of infectious agents in the pathogenesis of MS. First, MS may not be a unitary dis-ease; in other words, it is quite possible that MS, even if of infectious etiology, may be caused by any of several agents whose interaction with the nervous system leads to a common final pathology. In this setting, it may thus be of great value to pursue an organism that may cause disease in a only a percentage of patients. Second, detection of an agent in MS tissue does not necessarily mean that it is of etiological importance. Coinfection with two pathogens, one of which might by itself be commensal, may be another mechanism producing demyelination. Third, it must be kept in mind that infections may precipitate relapses in MS in nonspecific fashion and that these organisms themselves may be of secondary importance. Finally, the search for etiological agents in MS has always, of necessity, been one of attempts to identify known agents using current technology. The possibility must thus always be kept in mind that MS may be caused either by an as yet unidentified agent or by a known agent that is not detectable by current methods. Confirmation that a given agent is involved in the pathogenesis of MS will require reproducible detection of the same organism by more than one laboratory. Demonstrating the presence of these organisms at the clinical onset of the disease prior to immunotherapy will be an important step in proving causation, as will development of standardized methods, used in uniform fashion by different laboratories, for the detection of antipathogen antibodies, pathogen-specific nucleic acid sequences, or viable organisms. At present, the etiology of MS, be it infectious, autoimmune, or both, remains one of the most important -- and most challenging -- questions in neurology.
Acknowledgment: This work is supported by the Research Service of the
Department of Veterans Affairs.