Coincident onset of multiple sclerosis and Herpes simplex virus 1 encephalitis: a case report

This case illustrates a possible relationship between HSV-1 encephalitis and MS.

Bearing in mind that association does not imply causation, some speculations about the etiology and pathophysiology of the two diseases can be made.

To our knowledge, while the onset of MS after hemithorax zoster, with intrathecal reactivation of HSV-1 and HHV-6 has been reported [4] this is the first description of a coincident onset of MS and HSV-1 encephalitis. Other reports have provided laboratory evidence of the intrathecal presence of HSV-1 at disease onset. This supports the possibility that, in an individual with a peculiar genetic predisposition, this presence may turn into overt HSV-1 encephalitis [5, 6]. However, other viruses such as the John Cunningham (JC) virus have been described as replicating in the cerebrospinal fluid during the first symptoms of MS [7] though a coincident onset of MS and progressive multifocal encaphalomyelitis have never been described to our knowledge.

Most interestingly, the HSV-1 encephalitis develops in individuals with inborn errors of immune response genes that impair central nervous system-intrinsic interferon alpha/beta production [8]. The therapeutic response of persons with MS to interferon beta suggests that a portion of the pathophysiology of the two diseases may be shared. This possibility may be supported also by the sharing of a predisposing gene, TRAF3, between the two conditions (though this speculation has to be taken with caution because the effects of the observed variants may not be the same) [8, 9].

The role of a genetic predisposition emerges also from studies in inbred mouse strains with variable degrees of resistance to EAE/HSV [10]. In these models, the lip inoculation of the virus causes either no disease, or isolated lesions, or a diffuse picture of demyelination, depending on the genetic background of the mice. Interestingly, the multifocal lesions in the susceptible mice were first observed when the virus could no longer be isolated from the CNS of the animals. This is in line with the diffuse worsening of the bona-fide demyelinating lesions observed in the patient, when the viral DNA became undetectable in the CSF. Both observations are in harmony with an immune-mediated process, triggered by the virus, in hosts with a susceptible genetic background. Other sequences of events cannot be excluded: the autoimmune damage might have been present before the HSV-1 infection with the latter being exacerbated by the corticosteroids course. Nonetheless, the effects of corticosteroids in these patients are debated, as clinical trials are ongoing to assess their therapeutic effects in overt HSV-1 encephalitis. Also the role played by the diffuse alteration of the blood brain barrier (somehow resembling an acute disseminated encephalomyelitis process, secondary to the HSV-1 infection) remains unclear in the context of the whole process. A longitudinal follow-up with, for example, IEF-overlay technique with radiolabeled HSV glycoprotein B (gB), for studying qualitative aspects of the HSV humoral immune response [11, 12], would have been of use but was not performed. More in general, as common pathophysiologies emerge between MS and host immune response to viruses, tests for the detection of antiviral antibodies may acquire more importance in the near future.

All in all, the hypothesis of a genetic background predisposing to HSV-1 encephalitis and to immune-mediated demyelination is supported by the coincidence of the two conditions in this patient, along with data from animal models and genetic studies.