Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Specialty Sites
    • COVID-19
    • Without Borders
    • Equity, Diversity, and Inclusion
    • Innovations in Care Delivery
    • Practice Current
  • Collections
    • Topics A-Z
    • Residents & Fellows
    • Infographics
    • Patient Pages
    • Null Hypothesis
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Specialty Sites
    • COVID-19
    • Without Borders
    • Equity, Diversity, and Inclusion
    • Innovations in Care Delivery
    • Practice Current
  • Collections
    • Topics A-Z
    • Residents & Fellows
    • Infographics
    • Patient Pages
    • Null Hypothesis
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center
  • Home
  • Articles
  • Issues

User menu

  • My Alerts
  • Log in

Search

  • Advanced search
Neurology Neuroimmunology & Neuroinflammation
Home
A peer-reviewed clinical and translational neurology open access journal
  • My Alerts
  • Log in
Site Logo
  • Home
  • Articles
  • Issues

Share

March 2021; 8 (2) EditorialOpen Access

Learning More About HHV-6 Encephalitis

Joseph R. Berger
First published January 12, 2021, DOI: https://doi.org/10.1212/NXI.0000000000000948
Joseph R. Berger
From the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Full PDF
Citation
Learning More About HHV-6 Encephalitis
Joseph R. Berger
Neurol Neuroimmunol Neuroinflamm Mar 2021, 8 (2) e948; DOI: 10.1212/NXI.0000000000000948

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
0

Share

  • Article
  • Info & Disclosures
Loading

In this issue of Neurology® Neuroimmunology & Neuroinflammation, a retrospective study using an institutional virology database addresses the clinical nature, radiologic findings, and biological underpinnings of human herpesvirus 6 (HHV-6) encephalitis. The data had been accumulated systematically over a decade and included all individuals from whom blood or CSF had tested positive for HHV-6 DNA. From a cohort of 926 individuals tested for HHV-6, 45 individuals met the criteria of HHV-6 febrile seizures or encephalitis. This population comprised 30 children or adolescents and 15 adults (older than 18 years old); 28 (62%) were immunocompromised and 17 (38%) were immunocompetent. Efforts were made to identify individuals with chromosomally integrated HHV-6 DNA (ciHHV-6) by testing hair follicles for the presence of HHV-6 DNA in those with exceedingly high copy numbers of HHV-6 DNA in blood and CSF.

HHV-6 was first recognized to be associated with human disease in 1988 when it was isolated from the peripheral blood mononuclear cells of children with exanthem subitum (roseola infantum).1 As with herpesviruses, HHV-6 is an enveloped, double-stranded DNA virus that has an electron-dense core surrounded by an icosahedral nucleocapsid. There are 2 variants of HHV-6, variant A and variant B, distinguished by nucleotide sequences, cellular tropism, and antibody reactivity. HHV-6 is a member of the beta human herpes virus family and establishes latency in a broad range of tissues including salivary glands, tonsils, kidneys, liver, and lymph nodes.2 Saliva is believed to be the major vector of transmission.3 HHV-6 is ubiquitous; more than 80% of the adult population4 has serologic evidence of previous infection. Unlike other herpesviruses, HHV-6 may chromosomally integrate and ciHHV-6 is found in approximately 1% of the population.5 As noted by the authors, the presence of ciHHV-6 may distort the numbers of patients labeled with febrile seizures or encephalitis attributed to HHV-6.

Primary infection with HHV-6 results in roseola, a self-limited disease in infants and children characterized by fever, rash, pharyngitis, and usually mild systemic symptoms lasting 3 days on average. Neurologic complications of primary HHV-6 infection include febrile seizures, a complication observed in 13% of infected children.6 These seizures may differ from febrile seizures accompanying other infections because they are more often partial or prolonged or associated with postictal paralysis.7 Occasionally, encephalitis, including cerebellitis8 and rhombencephalitis9 may accompany roseola.

The prototypical HHV-6 encephalitis in adults is a limbic encephalitis that follows hematopoietic stem cell transplantation (HSCT). This entity has been referred to as post-transplantation acute limbic encephalitis (PALE). PALE is characterized by fever, behavioral changes, and seizures with medial temporal lobe abnormalities typically seen on brain MRI. As the authors of this study demonstrate, the limbic abnormalities on MRI are not universally present; only 2-thirds of their patients had brain MRI abnormalities, and their appearance may require several days from symptom onset to develop. Quite reasonably, the authors recommend that all HSCT recipients with altered mental status or seizures have CSF HHV-6 studies. They emphasize the value of detecting HHV-6 in the blood in suspected cases because not all the patients with unexplained neurologic symptoms attributed to HHV-6 after HSCT demonstrated viral DNA in their CSF.

Although individual case reports of meningoencephalitis10 and focal encephalitis11 attributed to HHV-6 have been reported in immunocompetent persons, the immunocompetent subjects with HHV-6 encephalitis in this study were all were infants younger than 2 years with primary infection. The authors propose that high viral copy numbers in the blood and CSF of immunocompetent with encephalitis most likely represents the presence of ciHHV-6, leading to misdiagnosis and a delay in establishing and treating the correct diagnosis. They recommend that testing for HHV-6 in immunocompetent individuals be limited to infants younger than 3 years of age developing seizures or encephalopathy in association with a fever who have suspected primary HHV-6 infection. Although some of the previous reports of HHV-6 encephalitis in immunocompetent individuals may have been the consequence of ciHHV-6, it is unlikely to account for all reported cases. For instance, in one elderly immunocompetent man with meningoencephalitis attributed to HHV-6, viral DNA was not only amplified from brain sections at the time of autopsy, but HHV-6 gp 102 protein was also the demonstrated by immunohistochemical studies of neurons and glial cells,12 an observation that would seem to refute that possibility that all HHV-6 encephalitis cases in immunocompetent subjects are due entirely to ciHHV-6. Therefore, additional confirmatory studies will be needed before the adoption of such a broad policy.

Study Funding

No targeted funding reported.

Disclosure

Disclosures available: Neurology.org/NN.

Footnotes

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • See page e942

  • Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

  1. 1.↵
    1. Yamanishi K,
    2. Okuno T,
    3. Shiraki K, et al
    . Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1988;1:1065–1067.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Agut H,
    2. Bonnafous P,
    3. Gautheret-Dejean A
    . Laboratory and clinical aspects of human herpesvirus 6 infections. Clin Microbiol Rev 2015;28:313–335.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Rhoads MP,
    2. Magaret AS,
    3. Zerr DM
    . Family saliva sharing behaviors and age of human herpesvirus-6B infection. J Infect 2007;54:623–626.
    OpenUrlPubMed
  4. 4.↵
    1. Saxinger C,
    2. Polesky H,
    3. Eby N, et al
    . Antibody reactivity with HBLV (HHV-6) in U.S. populations. J Virol Methods 1988;21:199–208.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Pellett PE,
    2. Ablashi DV,
    3. Ambros PF, et al
    . Chromosomally integrated human herpesvirus 6: questions and answers. Rev Med Virol 2012;22:144–155.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Hall CB,
    2. Long CE,
    3. Schnabel KC, et al
    . Human herpesvirus-6 infection in children. A prospective study of complications and reactivation. N Engl J Med 1994;331:432–438.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Suga S,
    2. Suzuki K,
    3. Ihira M, et al
    . Clinical characteristics of febrile convulsions during primary HHV-6 infection. Arch Dis Child 2000;82:62–66.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Abu Sitta E,
    2. Khazan A,
    3. Luttmann K,
    4. Hanrahan J
    . HHV-6: an unusual cause of cerebellar ataxia. BMJ Case Rep 2020;13:e234303.
    OpenUrl
  9. 9.↵
    1. Crawford JR,
    2. Kadom N,
    3. Santi MR,
    4. Mariani B,
    5. Lavenstein BL
    . Human herpesvirus 6 rhombencephalitis in immunocompetent children. J Child Neurol 2007;22:1260–1268.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Birnbaum T,
    2. Padovan CS,
    3. Sporer B, et al
    . Severe meningoencephalitis caused by human herpesvirus 6 type B in an immunocompetent woman treated with ganciclovir. Clin Infect Dis 2005;40:887–889.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. McCullers JA,
    2. Lakeman FD,
    3. Whitley RJ
    . Human herpesvirus 6 is associated with focal encephalitis. Clin Infect Dis 1995;21:571–576.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Portolani M,
    2. Tamassia MG,
    3. Gennari W, et al
    . Post-mortem diagnosis of encephalitis in a 75-year-old man associated with human herpesvirus-6 variant A. J Med Virol 2005;77:244–248.
    OpenUrlCrossRefPubMed
View Abstract

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

NOTE: All contributors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.nn.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.

  • Stay timely. Submit only on articles published within the last 8 weeks.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • 200 words maximum.
  • 5 references maximum. Reference 1 must be the article on which you are commenting.
  • 5 authors maximum. Exception: replies can include all original authors of the article.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Letters

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Letters Submission Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Study Funding
    • Disclosure
    • Footnotes
    • References
  • Info & Disclosures

Related Articles

  • Human Herpesvirus 6 Encephalitis in Immunocompetent and Immunocompromised Hosts

Topics Discussed

  • All Epilepsy/Seizures
  • Encephalitis
  • Meningitis

Alert Me

  • Alert me when eletters are published
Advertisement
Neurology - Neuroimmunology Neuroinflammation: 8 (2)

Articles

  • Articles
  • Issues
  • Popular Articles

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology: Neuroimmunology & Neuroinflammation
Online ISSN: 2332-7812

© 2021 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise