Coincident onset of multiple sclerosis and Herpes simplex virus 1 encephalitis: a case report
https://doi.org/10.1186/s40893-017-0023-5
© The Author(s). 2017
Received: 2 February 2017
Accepted: 30 March 2017
Published: 28 April 2017
Abstract
Background
Along with vitamin D, smoking, body mass index and others, Epstein Barr virus, other herpesviruses and human endogenous retroviruses represent plausible environmental risk factors for multiple sclerosis. However, it is difficult to obtain direct proof of their involvement in the etiology of this condition.
Case presentation
In order to contribute further evidence of the importance of these viruses, and speculate about disease-relevant interactions between these agents and a predisposed genetic background of the host, we describe the temporal association between multiple sclerosis onset and Herpes simplex 1-encephalitis in a female patient.
Conclusions
This case illustrates a possible relationship between HSV-1 encephalitis and multiple sclerosis. Bearing in mind that association does not imply causation, some speculations about the etiology and pathophysiology of the two diseases can be made. 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.
Keywords
Background
Heritable and nonheritable factors, and their interactions, may be responsible for the autoimmune response that leads to multiple sclerosis (MS) [1].
Genome-wide association studies are improving our understanding of the heritable basis of the disease, most probably involving subtle defects of the regulation of transcription [2]. Though these studies are indeed advancing our knowledge, the nonheritable or “environmental” component of the risk shows a slower progress. Among the environmental risk factors, viruses are intensively investigated as possible culprits [3]. Human endogenous retroviruses such as MSRV have attracted interest because of their capacity to hide by integrating in the human DNA and then trigger immunological mechanisms: a scenario that is compatible with the long standing difficulties in detecting any infectious agent in the MS central nervous system. On the other hand, herpesviruses are sound candidates as well, because of neurotropism and, in the case of Epsein Barr virus, extraordinary ability to modulate the human immune response.
In order to contribute further evidence of the importance of these viruses, and speculate about disease-relevant interactions between these agents and a predisposed genetic background of the host, we describe the temporal association between MS onset and Herpes simplex 1 (HSV)-encephalitis in a female patient.
Case Presentation
a Axial FLAIR MRI that highlights hyperintense left periventricular areas; b left periventricular and frontal subcortical; c right cerebellar peduncle
She was then treated with methylprednisolone 1 g intravenously for five days with a clear improvement of the symptom. Ten days after the completion of the corticosteroid course, she presented fever, severe headache and confusion. A brain CT scan was obtained, highlighting a hypodense area that involved right temporal pole, insula and hippocampus. She was then hospitalized and her cerebrospinal fluid (CSF) tested positive for HSV-1 DNA. All other CSF tests were negative including: Cytomegalovirus, Varicella Zoster, Epstein Barr virus, John Cunningham virus, enteroviruses, Toxoplasma, Cryptococcus, Mycobacterium tuberculosis and Treponema, oligoclonal bands. With the exception of a positive test for recent HSV-1 infection, all other serologies were negative for recent infections including: Coxiella, Coxsackie, Chlamydia pneumoniae, Borrelia burgdoferi, Mycoplasma pneumoniae, echovirus and adenovirus. Peripheral blood screening tests for autoimmune diseases were negative.
Axial T2 image showing hyperintensity of the right temporal lobe and right brainstem with less obvious contralateral alterations
Axial FLAIR showing the temporal encephalitis outcome
In view of the apparent flare of the “autoimmune” condition, the patient was started on intravenous immunoglobulins (IVIG) at 0.4gr/kg/daily for 5 days and Methilprendisolone 40mg/daily for 15 days. She also continued therapy with Valacyclovir 3g/ daily.
Cervical spinal cord sagittal image showing demyelinating hyperintense areas at C4
Comparison of MRIs obtained at 4 months (a) and at 18 months after onset (b) showing a reduction of the areas in MS-typical regions though the lesion load remains higher compared with the first MRI (Fig. 1)
Discussion and conclusions
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.
Declarations
Acknowledgements
The authors would like to thank the patient for consent for publication.
Funding
No funding was received.
Availability of data and material
Not applicable.
Authors’ contributions
MCB, MS and GR: contributed equally for writing and critical reading of the manuscript; GT provided interpretation of MRI imaging; AF, SR, MF, RR: provided critical reading of the manuscript. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Informed consent was obtained from the patient for publication of this case report and any accompanying images.
Ethics approval and consent to participate
Not applicable.
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Authors’ Affiliations
References
- Bordi I, Ricigliano VA, Umeton R, Ristori G, Grassi F, Crisanti A, Sutera A, Salvetti M. Noise in multiple sclerosis: unwanted and necessary. Ann Clin Transl Neurol. 2014;1(7):502–11. doi:10.1002/acn3.72. Epub 2014 Jun 19.View ArticlePubMedPubMed CentralGoogle Scholar
- Farh KK, Marson A, Zhu J, Kleinewietfeld M, Housley WJ, Beik S, Shoresh N, Whitton H, Ryan RJ, Shishkin AA, Hatan M, Carrasco-Alfonso MJ, Mayer D, Luckey CJ, Patsopoulos NA, De Jager PL, Kuchroo VK, Epstein CB, Daly MJ, Hafler DA, Bernstein BE. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015;518(7539):337–43. doi:10.1038/nature13835. Epub 2014 Oct 29.View ArticlePubMedGoogle Scholar
- Salvetti M, Giovannoni G, Aloisi F. Epstein-Barr virus and multiple sclerosis. Curr Opin Neurol. 2009;22(3):201–6. doi:10.1097/WCO.0b013e32832b4c8d.View ArticlePubMedGoogle Scholar
- Ferrò MT, Franciotta D, Prelle A, Bestetti A, Cinque P. Active intrathecal herpes simplex virus type 1 (HSV-1) and human herpesvirus-6 (HHV-6) infection at onset of multiple sclerosis. J Neurovirol. 2012;18:437–40. doi:10.1007/s13365-012-0110-5.View ArticlePubMedGoogle Scholar
- Franciotta D, Bestetti A, Sala S, Perucca P, Jarius S, Price RW, Di Stefano AL, Cinque P. Broad screening for human herpesviridae DNA in multiple sclerosis cerebrospinal fluid and serum. Acta Neurol Belg. 2009;109:277–82.PubMedGoogle Scholar
- Bergström T, Andersen O, Vahlne A. Isolation of herpes simplex virus type 1 during first attack of multiple sclerosis. Ann Neurol. 1989;26:283–5. doi:10.1002/ana.410260218.View ArticlePubMedGoogle Scholar
- Ribeiro T, Fleury MJ, Granieri E, et al. Investigation of the prevalence of antibodies against neurotropic polyomaviruses BK, JC and SV40 in sera from patients affected by multiple sclerosis. Neurol Sci. 2010;31(4):517–21. doi:10.1007/s10072-010-0353-y.View ArticlePubMedGoogle Scholar
- Alcaïs A, Abel L, Casanova JL. Human genetics of infectious diseases: between proof of principle and paradigm. J Clin Invest. 2009;119:9.View ArticleGoogle Scholar
- Zhang SY, Casanova JL. Inborn errors underlying herpes simplex encephalitis: From TLR3 to IRF3. INSIGHTS |. J Exp Med. 2015;24.Google Scholar
- Kastrukoff LF, Lau AS, Kim SU. Multifocal CNS demyelination following peripheral inoculation with herpes simplex virus type 1. Ann Neurol. 1987;22(1):52–9.View ArticlePubMedGoogle Scholar
- Grimaldi LME, Roos RP, Manservigi R, Spear PG, Lakeman FD, Whitley RJ. An Isoelectric Focusing Study in Herpes Simplex Virus Encephalitis. Ann Neurol. 1988;24:2.Google Scholar
- Martino GV, Grimaldi LME, Franciotta DM, Piccolo G, Brustia R, Minali L, GV M d'E. Isoelectric focusing herpes simplex virus-gB overlay study in brainstem encephalitis. Acta Neurol Scand. 1990;82(6):364–7.View ArticlePubMedGoogle Scholar