Central Nervous System Infections of Herpesvirus Family

https://doi.org/10.1016/j.nic.2007.12.001Get rights and content

Herpesviruses are one of the most common groups of pathogens causing central nervous system infections in humans. They mostly cause encephalitis, meningitis, or myelitis in immunocompetent and immunocompromised patients. Children, adults, and the elderly can all be affected. Although contrast-enhanced CT is more widely used for diagnosis, contrast-enhanced MR imaging combined with diffusion-weighted imaging is superior to CT in the detection of early changes and the real extent of the disease, and in assessing prognosis and monitoring response to antiviral treatment. More sophisticated techniques, such as MR spectroscopy and perfusion imaging, can aid in the differential diagnosis of herpesvirus infections from other tumoral, demyelinating, and ischemic processes.

Section snippets

Mechanism of the herpesvirus infections

The skin, conjunctiva, and mucosa of the oropharynx or genitalia are the primary entry sites for HHV. Following replication in the inoculation site, they usually cause a hematogenous spread, called a viremia, to distant tissues [4]. All herpesviruses show some kind of neurotropism, either by hematogenous spread or neuronal transmission [1]. The neurovirulence of herpesviruses is mediated by the thymidine kinase gene and the termini of the L component [2]. The γ134.5 gene is required for the

Herpes simplex virus type 1

HSV is the most common cause of acute fatal sporadic encephalitis in human beings [15], [25], [26], [27]. It usually produces focal encephalitis rather than diffuse or nonfocal disease [15]. The actual vector of HSE is HSV-1 in most patients (>90%) and HSV-2 in the remainder [26], [28]. HSE was thought to account for 10% to 20% of all viral encephalitis, with an annual incidence of 1/250,000 to 500,000, before the introduction of West Nile virus encephalitis [25], [27]. Mainly, HSE is the

Herpes simplex virus type 2

HSV-2 mainly causes genital herpes and establishes latency in the sacral dorsal route ganglia. The virus can sexually infect the mouth and cause facial herpes [15]. Other manifestations of HSV-2 infection (eg, herpetic whitlow) are much less common. In the CNS, HSV-2 essentially causes neonatal encephalitis by infecting the neonate during its passage through the infected maternal birth canal, like other agents causing toxoplasmosis, other enteroviral infections, rubella, cytomegalic inclusion

Varicella zoster virus

The VZV actually causes acute febrile exanthematous illness (called varicella or chickenpox) in children. Following primary infection, VZV shows latency in the cranial nerve ganglia (usually trigeminal or geniculate), or the dorsal root ganglia (usually the thoracic level) throughout the lifetime of the host [16]. CNS complications of varicella infection, including cerebellar ataxia, meningoencephalitis, transverse myelitis, and aseptic meningitis, are rare, occurring in less than 1% of

Epstein-Barr virus

EBV frequently causes acute infectious mononucleosis and, rarely, chronic active EBV infection. Additionally, EBV is associated with nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin's disease, and lymphoproliferative disorders in immunocompromised patients [134]. Although CNS complications of EBV have been estimated to occur in 1% to 5% of patients who have infectious mononucleosis [135], the real burden of this entity is probably underestimated [136]. EBV involvement of the CNS causes a

Cytomegalovirus

Most of the immunocompetent population (60%–70%) in developed countries is infected with CMV by as early as 6 years of age and the rest become infected during their lifetime. Congenital CMV infections, presented as neonatal encephalitis or meningitis, are usually mortal and caused by transplacental seeding of the virus. Besides congenital CMV infection, the cellular and molecular mechanisms of CMV-related persistent infection, latency, and reactivation are not well understood. Although

Human herpesvirus type 6 and type 7

HHV-6 and HHV-7, together with CMV, belong to the Roseolovirus genus of the beta herpesvirus subfamily, and HHV-6 has two variants, namely HHV-6A and HHV-6B [159]. HHV-6, and occasionally HHV-7, cause roseola infantum (exanthema subitum) in children [21], [159]. Primary HHV-6 and HHV-7 infection occurs in early childhood, and serologic studies indicate that virtually all children have been infected with HHV-6 by 3 years of age, and 70% and 85% of immunocompetent children have been infected with

Human herpesvirus type 8

HHV-8, also known as Kaposi's sarcoma–associated herpesvirus, is a gamma herpesvirus associated with all forms of Kaposi's sarcoma in immunocompromised and immunocompetent patients, body cavity–based lymphoma, and multicentric Castleman disease [138]. HHV-8 is strongly neurotropic and, like HHV-6, some of its specific sequences have been detected in postmortem brain specimens from multiple sclerosis patients [168]. HHV-8 has been detected in the dorsal root ganglia of Kaposi's sarcoma patients,

B virus (Herpesvirus simiae)

The B virus (Herpesvirus simiae) is an alpha herpesvirus that is endemic among monkeys of the Macaca species and usually causes vesicles or ulcers similar to those associated with HSV-1 infection on the oral mucosal surfaces, skin, and conjunctiva of these primates [174]. The significance of the B virus is that it can cause fatal infections in human beings who work with these animals. Unlike HSE, the B virus can involve any region of the CNS and can cause fatal encephalitis, encephalomyelitis,

Summary

Although some MR imaging features of herpesvirus infections are diagnostic, as detailed above, the radiologic findings of herpetic infections usually do not allow the making of an exact differential diagnosis of clinical pictures caused by different subgroups of herpes family. Radiologic findings should be correlated with clinical and other laboratory findings, such as EEG and CSF findings, or herpesvirus DNA in CSF, augmented by a PCR test.

The characteristic imaging patterns of herpesvirus

References (175)

  • R.N. Sener

    Herpes simplex encephalitis: diffusion MR imaging findings

    Comput Med Imaging Graph

    (2001)
  • R.N. Sener

    Diffusion MRI in Rasmussen's encephalitis, herpes simplex encephalitis, and bacterial meningoencephalitis

    Comput Med Imaging Graph

    (2002)
  • Y. Schlesinger et al.

    Expanded spectrum of herpes simplex encephalitis in childhood

    J Pediatr

    (1995)
  • L. Heiner et al.

    Diffusion-weighted MR imaging findings in a patient with herpes simplex encephalitis

    Eur J Radiol

    (2003)
  • H. Gumus et al.

    Unusual presentation of herpes simplex virus encephalitis: bilateral thalamic involvement and normal imaging of early stage of the disease

    Am J Emerg Med

    (2007)
  • J. Takanashi et al.

    Longitudinal MR imaging and proton MR spectroscopy in herpes simplex encephalitis

    J Neurol Sci

    (1997)
  • L. Corey et al.

    Difference between herpes simplex virus type 1 and type 2 neonatal encephalitis in neurological outcome

    Lancet

    (1988)
  • J. Launes et al.

    Diagnosis of acute herpes simplex encephalitis by brain perfusion single photon emission computed tomography

    Lancet

    (1988)
  • J.W. Park et al.

    Detection of acute Epstein Barr virus cerebellitis using sequential brain HMPAO-SPECT imaging

    Clin Neurol Neurosurg

    (2004)
  • J.S. Burgos et al.

    Non-invasive bioluminescence imaging for monitoring herpes simplex virus type 1 hematogenous infection

    Microbes Infect

    (2006)
  • Y. Mochizuki et al.

    Acute limbic encephalitis: a new entity?

    Neurosci Lett

    (2006)
  • B. Roizman et al.

    Herpes simplex viruses and their replication

  • R.D. Tien et al.

    Herpes trigeminal neuritis and rhombencephalitis on Gd-DTPA-enhanced MR imaging

    AJNR Am J Neuroradiol

    (1990)
  • J.M. Markert et al.

    Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial

    Gene Ther

    (2000)
  • J.M. Markert et al.

    Genetically engineered HSV in the treatment of glioma: a review

    Rev Med Virol

    (2000)
  • R.T. Johnson et al.

    Pathogenesis of viral infections of the nervous system

    N Engl J Med

    (1968)
  • B.K. Kleinschmidt-DeMasters et al.

    The expanding spectrum of herpesvirus infections of the nervous system

    Brain Pathol

    (2001)
  • B. Roizman et al.

    An inquiry into the mechanisms of herpes simplex virus latency

    Annu Rev Microbiol

    (1987)
  • R.J. Whitley et al.

    Herpes simplex virus infections of the central nervous system: therapeutic and diagnostic considerations

    Clin Infect Dis

    (1995)
  • A. Nair et al.

    Modulation of microglia and CD8+ T cell activation during the development of stress-induced herpes simplex virus type-1 encephalitis

    Brain Behav Immun

    (2007)
  • R.J. Danaher et al.

    Reactivation from quiescence does not coincide with a global induction of herpes simplex virus type 1 transactivators

    Virus Genes

    (2006)
  • G. Palu et al.

    Molecular basis of the interactions between herpes simplex viruses and HIV-1

    Herpes

    (2001)
  • K.L. Tyler

    Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's

    Herpes

    (2004)
  • B.K. Kleinschmidt-DeMasters et al.

    Varicella-Zoster virus infections of the nervous system: clinical and pathologic correlates

    Arch Pathol Lab Med

    (2001)
  • T. Weber et al.

    Clinical implications of nucleic acid amplification methods for the diagnosis of viral infections of the nervous system

    J Neurovirol

    (1996)
  • P. Cinque et al.

    Cytomegalovirus infections of the nervous system

    Intervirology

    (1997)
  • D.H. Gilden et al.

    Neurologic complications of varicella zoster virus reactivation

    N Engl J Med

    (2000)
  • P. Portegies et al.

    Epstein-Barr virus and the nervous system

    Curr Opin Neurol

    (2000)
  • D.W. Kimberlin

    Neuroinvasion of human herpesviruses 6 and 7

    Herpes

    (1999)
  • A. Simmons

    Herpesviruses and multiple sclerosis

    Herpes

    (2001)
  • R.B. Pyles

    The association of herpes simplex virus and Alzheimer's disease: a potential synthesis of genetic and environmental factors

    Herpes

    (2001)
  • N.E. Soto et al.

    Chronic fatigue syndrome and herpesviruses: the fading evidence

    Herpes

    (2000)
  • L. Corey et al.

    Infections with herpes simplex viruses (2)

    N Engl J Med

    (1986)
  • R.J. Whitley et al.

    Herpes simplex encephalitis. Clinical assessment

    JAMA

    (1982)
  • E. Aurelius et al.

    Encephalitis in immunocompetent patients due to herpes simplex virus type 1 or 2 as determined by type-specific polymerase chain reaction and antibody assays of cerebrospinal fluid

    J Med Virol

    (1993)
  • R.L. Hamilton et al.

    Herpes simplex virus brainstem encephalitis in an AIDS patient

    Clin Neuropathol

    (1995)
  • R.J. Whitley et al.

    Herpes simplex encephalitis: vidarabine therapy and diagnostic problems

    N Engl J Med

    (1981)
  • R.J. Whitley et al.

    Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group

    JAMA

    (1989)
  • T. Hori et al.

    Chronic herpes simplex encephalitis with somnambulism: CT, MR and SPECT findings

    Jpn J Psychiatry Neurol

    (1990)
  • J.B. Smith et al.

    A distinctive clinical EEG profile in herpes simplex encephalitis

    Mayo Clin Proc

    (1975)
  • Cited by (70)

    • Brainstem Encephalitis. The Role of Imaging in Diagnosis

      2021, Current Problems in Diagnostic Radiology
      Citation Excerpt :

      Herpes simplex virus encephalitis has a high mortality rate (>70%) in untreated and poorly treated patients. HSV has a high affinity for the limbic system, which is often bilateral but asymmetric, extratemporal involvement can be seen in more than half of the patients.12 The involvement of the brainstem is not uncommon; it can get involved through the retrograde transmission of the virus through the cisternal segment of the trigeminal nerve or rarely via the facial nerve.

    • Diffusion-Weighted Imaging is Key to Diagnosing Specific Diseases

      2021, Magnetic Resonance Imaging Clinics of North America
    • Central Nervous System Lesions in Immunocompromised Patients

      2019, Radiologic Clinics of North America
    View all citing articles on Scopus
    View full text