Herpes Simplex Encephalitis Workup

  • Author: Wayne E Anderson, DO; Chief Editor: Karen L Roos, MD   more...
 
Updated: Jun 17, 2011
 

Approach Considerations

In suspected herpes simplex encephalitis (HSE), the workup must be initiated rapidly and should not delay treatment. General laboratory studies are not helpful in diagnosis but may show evidence of infection or detect renal disease (in which case treatment must be adjusted). A high index of suspicion is required in all immunocompromised patients with febrile encephalopathy.

No pathognomonic clinical findings are associated with HSE. Focal neurologic deficits, cerebrospinal fluid (CSF) pleocytosis, and abnormalities on computed tomography (CT) scanning may be absent initially. The diagnosis can be confirmed only by means of polymerase chain reaction (PCR) or brain biopsy.

Diagnostic modalities for neonatal HSE are similar to those for HSE in older children and adults.

Go to Imaging in Herpes Encephalitis for complete information on this topic.

Next

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) of the brain is the preferred imaging study. Proton-density and T2 images may be more helpful than T1 images. MRI can noninvasively establish many of the potential alternative diagnoses of HSE.

Abnormalities are found in 90% of patients with HSE; MRI may be normal early in the course of illness. Temporal lobe involvement (see the images below), sometimes hemorrhagic, and early involvement of white matter are typical. The inferomedial portion of the temporal lobe is most commonly affected on MRI, sometimes in association with abnormalities of the cingulate gyrus.

Axial proton density-weighted image in 62-year-oldAxial proton density-weighted image in 62-year-old woman with confusion and herpes encephalitis shows T2 hyperintensity involving right temporal lobe. Axial gadolinium-enhanced T1-weighted image revealAxial gadolinium-enhanced T1-weighted image reveals enhancement of right anterior temporal lobe and parahippocampal gyrus. At right anterior temporal tip is hypointense, crescentic region surrounded by enhancement consistent with small epidural abscess. Axial diffusion-weighted image reveals restricted Axial diffusion-weighted image reveals restricted diffusion in left medial temporal lobe consistent with herpes encephalitis. This patient also had positive result on polymerase chain reaction assay for herpes simplex virus, which is both sensitive and specific. In addition, patient had periodic lateralized epileptiform discharges on electroencephalography, which supports diagnosis of herpes encephalitis.

Findings of localized temporal abnormalities are highly suggestive of HSE, but again, confirmation of the diagnosis depends on the identification of herpes simplex virus (HSV) by means of PCR or brain biopsy.

Previous
Next

Computed Tomography

Approximately one third of patients with HSE have normal CT findings on presentation. Head CT may show changes in the temporal and/or frontal lobe, but CT is less sensitive than MRI.

Low-density lesions may be found in two thirds of cases, especially in the temporal lobes, but they may not appear until 3-4 days after onset. Edema and hemorrhages may be present. After 1 week, contrast enhancement may be detectable.

Previous
Next

Electroencephalography

Electroencephalography (EEG), though lacking in specificity (32%), has 84% sensitivity to abnormal patterns in HSE. Focal abnormalities (eg, spike and slow- or periodic sharp-wave patterns over the involved temporal lobes) or diffuse slowing may be observed.

Periodic complexes and periodic lateralizing epileptiform discharges (PLEDs), in the proper clinical context, are strongly suggestive of HSE. However, Beneto et al reported 9 patients with confirmed HSE who had no PLED activity or had other EEG patterns.[29]

Previous
Next

Analysis of Cerebrospinal Fluid

Once a space-occupying lesion has been excluded by imaging, lumbar puncture always should be performed in suspected HSE. In general, CSF yield is proportional to the volume analyzed; an adequate volume of CSF should be obtained (>10 mL).

Acutely, a typical “viral profile” is identified. Red blood cells (RBCs) and xanthochromia may be seen. Patients typically have mononuclear pleocytosis of 10-500 white blood cells (WBCs)/µL (average, 100 WBCs/µL). As a result of the hemorrhagic nature of the underlying pathologic process, the RBC count may be elevated (10-500/µL). Protein levels are elevated to the range of 60-700 mg/dL (average, 100 mg/dL). Glucose values may be normal or mildly decreased (30-40 mg/dL).

In about 5-10% of patients, especially children, initial CSF results may be normal.[30] However, on serial examinations, the cell counts and protein values increase.

Viral cultures of CSF are rarely positive and should not be relied on to confirm the diagnosis. However, HSV can be cultured from the CSF in about one third of affected neonates.

Previous
Next

Polymerase chain reaction

CSF should be sent for HSV-1 and HSV-2 polymerase chain reaction (PCR) study. PCR analysis of CSF for the detection of HSV DNA has virtually replaced brain biopsy as the criterion standard for diagnosis.[31, 32] Schloss and colleagues report that whereas quantitative PCR is more rational than a nested PCR, the former has little prognostic use.[33]

PCR is highly sensitive (94-98%) and specific (98-100%). Results become positive within 24 hours of the onset of symptoms and remain positive for at least 5-7 days after the start of antiviral therapy.

Clinical severity and outcome appear to correlate with viral load as assessed by quantitative PCR techniques,[34] but not all investigators have confirmed this correlation.[35]

False-negative findings may occur early in the course of the disease when viral DNA levels are low (within 72 hours of the onset of symptoms) or when blood is present in the CSF, because hemoglobin may interfere with PCR.[36]

Pretest probability should be considered in interpretation of results. A negative result obtained less than 72 hours after the onset of symptoms in a patient with a high pretest probability (on the basis of fever, focal neurologic abnormalities, or CSF pleocytosis) should be repeated.

False-positive test results are rare and usually reflect accidental contamination of the specimen in the laboratory.

Previous
Next

Brain Biopsy

Brain biopsy was once considered the only definitive means of diagnosing HSE. The results of brain biopsy can also establish alternative diagnoses, both treatable (eg, brain tumor) and nontreatable (eg, non-HSV viral encephalitis). Currently, with the advent of PCR technology, the role of brain biopsy is diminishing. Studies have demonstrated that PCR testing of CSF is as accurate as brain biopsy in confirming the diagnosis of HSE.

When the diagnosis of HSE cannot be established by other means (eg, when lumbar puncture is precluded or nondiagnostic), brain biopsy can yield a definitive diagnosis and may be considered. However, with the availability of nontoxic and effective antiviral medications, brain biopsy is rarely used today. The procedure carries a complication rate of about 3%.

Orbitofrontal or limbic encephalitis may be seen. One hallmark of the condition is significant hemorrhage in these locations. On pathology specimens, Cowdry A inclusions are seen.

Previous
Next

Other Tests

Serologic analysis

Serologic evaluation of blood or CSF may be useful for retrospective diagnosis, but it has no role in the acute diagnosis and treatment of patients.

Strategies based on increases in antibody levels and on the ratio of antibody levels in serum and CSF have not proven to be clinically useful.

Tzanck preparations

HSV can sometimes be confirmed by Tzanck preparations taken from vesicular lesions in neonates with herpes simplex encephalitis.

Quantification of intrathecal antibodies

Intrathecal antibodies can be quantified, thus giving evidence for a central nervous system (CNS) antibody response.

Previous
Proceed to Treatment & Management
 
 
Contributor Information and Disclosures
Author

Wayne E Anderson, DO  Assistant Professor of Internal Medicine/Neurology, College of Osteopathic Medicine of the Pacific Western University of Health Sciences; Clinical Faculty in Family Medicine, Touro University College of Osteopathic Medicine; Clinical Instructor, Departments of Neurology and Pain Management, California Pacific Medical Center

Wayne E Anderson, DO is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Society of Law, Medicine & Ethics, California Medical Association, and San Francisco Medical Society

Disclosure: Cephalon Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; King Honoraria Speaking and teaching; Forest Honoraria Speaking and teaching

Specialty Editor Board

Ramon Diaz-Arrastia, MD, PhD  Professor, Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Southwestern Medical School; Director, North Texas TBI Research Center, Comprehensive Epilepsy Center, Parkland Memorial Hospital

Ramon Diaz-Arrastia, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, New York Academy of Sciences, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting

Chief Editor

Karen L Roos, MD  John and Nancy Nelson Professor of Neurology, Professor of Neurological Surgery, Department of Neurology, Indiana University School of Medicine

Karen L Roos, MD is a member of the following medical societies: American Academy of Neurology and American Neurological Association

Disclosure: Nothing to disclose.

References

  1. Whitley RJ. Herpes simplex encephalitis: adolescents and adults. Antiviral Res. Sep 2006;71(2-3):141-8. [Medline].

  2. Whitley RJ, Kimberlin DW. Herpes simplex encephalitis: children and adolescents. Semin Pediatr Infect Dis. Jan 2005;16(1):17-23. [Medline].

  3. Tyler KL. Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's. Herpes. Jun 2004;11 Suppl 2:57A-64A. [Medline].

  4. Wasay M, Mekan SF, Khelaeni B, Saeed Z, Hassan A, Cheema Z, et al. Extra temporal involvement in herpes simplex encephalitis. Eur J Neurol. Jun 2005;12(6):475-9. [Medline].

  5. Aurelian L. HSV-induced apoptosis in herpes encephalitis. Curr Top Microbiol Immunol. 2005;289:79-111. [Medline].

  6. DeBiasi RL, Kleinschmidt-DeMasters BK, Richardson-Burns S, Tyler KL. Central nervous system apoptosis in human herpes simplex virus and cytomegalovirus encephalitis. J Infect Dis. Dec 1 2002;186(11):1547-57. [Medline].

  7. Esiri MM. Herpes simplex encephalitis. An immunohistological study of the distribution of viral antigen within the brain. J Neurol Sci. May 1982;54(2):209-26. [Medline].

  8. Cinque P, Vago L, Marenzi R, Giudici B, Weber T, Corradini R, et al. Herpes simplex virus infections of the central nervous system in human immunodeficiency virus-infected patients: clinical management by polymerase chain reaction assay of cerebrospinal fluid. Clin Infect Dis. Aug 1998;27(2):303-9. [Medline].

  9. Fodor PA, Levin MJ, Weinberg A, Sandberg E, Sylman J, Tyler KL. Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF. Neurology. Aug 1998;51(2):554-9. [Medline].

  10. Osih RB, Brazie M, Kanno M. Multifocal herpes simplex virus type 2 encephalitis in a patient with AIDS. AIDS Read. Feb 2007;17(2):67-70. [Medline].

  11. Baringer JR, Pisani P. Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction. Ann Neurol. Dec 1994;36(6):823-9. [Medline].

  12. Mitchell BM, Stevens JG. Neuroinvasive properties of herpes simplex virus type 1 glycoprotein variants are controlled by the immune response. J Immunol. Jan 1 1996;156(1):246-55. [Medline].

  13. Geiger KD, Nash TC, Sawyer S, Krahl T, Patstone G, Reed JC, et al. Interferon-gamma protects against herpes simplex virus type 1-mediated neuronal death. Virology. Nov 24 1997;238(2):189-97. [Medline].

  14. Cathomas R, Pelosi E, Smart J, Murray N, Simmonds P. Herpes simplex encephalitis as a complication of adjuvant chemotherapy treatment for breast cancer. Clin Oncol (R Coll Radiol). Jun 2005;17(4):292-3. [Medline].

  15. Kohl S. Herpes Simplex Virus. In: Behrman RE, Kliegman RM, Jenson HB. Behrman: Nelson Textbook of Pediatrics. 17th ed. Philadelphia: Saunders; 2004.

  16. Kimberlin D. Herpes simplex virus, meningitis and encephalitis in neonates. Herpes. Jun 2004;11 Suppl 2:65A-76A. [Medline].

  17. Whitley RJ, Soong SJ, Dolin R, Galasso GJ, Ch'ien LT, Alford CA. Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. National Institute of Allergy and Infectious Diseases collaborative antiviral study. N Engl J Med. Aug 11 1977;297(6):289-94. [Medline].

  18. Utley TF, Ogden JA, Gibb A, McGrath N, Anderson NE. The long-term neuropsychological outcome of herpes simplex encephalitis in a series of unselected survivors. Neuropsychiatry Neuropsychol Behav Neurol. Jul 1997;10(3):180-9. [Medline].

  19. Elbers JM, Bitnun A, Richardson SE, Ford-Jones EL, Tellier R, Wald RM, et al. A 12-year prospective study of childhood herpes simplex encephalitis: is there a broader spectrum of disease?. Pediatrics. Feb 2007;119(2):e399-407. [Medline].

  20. Shelley BP, Raniga SB, Al-Khabouri J. An unusual late complication of intracerebral haematoma in herpes encephalitis after successful acyclovir treatment. J Neurol Sci. Jan 31 2007;252(2):177-80. [Medline].

  21. Marschitz I, Rödl S, Gruber-Sedlmayr U, Church A, Giovannoni G, Zobel G, et al. Severe chorea with positive anti-basal ganglia antibodies after herpesencephalitis. J Neurol Neurosurg Psychiatry. Jan 2007;78(1):105-7. [Medline]. [Full Text].

  22. Sköldenberg B, Aurelius E, Hjalmarsson A, Sabri F, Forsgren M, Andersson B, et al. Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults. J Neurol. Feb 2006;253(2):163-70. [Medline].

  23. Whitley RJ, Cobbs CG, Alford CA Jr, Soong SJ, Hirsch MS, Connor JD, et al. Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group. JAMA. Jul 14 1989;262(2):234-9. [Medline].

  24. Whitley RJ, Soong SJ, Linneman C Jr, Liu C, Pazin G, Alford CA. Herpes simplex encephalitis. Clinical Assessment. JAMA. Jan 15 1982;247(3):317-20. [Medline].

  25. Ku A, Lachmann EA, Nagler W. Selective language aphasia from herpes simplex encephalitis. Pediatr Neurol. Sep 1996;15(2):169-71. [Medline].

  26. McGrath NM, Anderson NE, Hope JK, Croxson MC, Powell KF. Anterior opercular syndrome, caused by herpes simplex encephalitis. Neurology. Aug 1997;49(2):494-7. [Medline].

  27. Mondal G, Kumar R, Ghosh JK, Basu K, Chatterjee S. Basal ganglia involvement in a child with herpes simplex encephalitis. Indian J Pediatr. Jul 2009;76(7):749-50. [Medline].

  28. Li JZ, Sax PE. HSV-1 encephalitis complicated by cerebral hemorrhage in an HIV-positive person. AIDS Read. Apr 2009;19(4):153-5. [Medline].

  29. Benetó A, Gómez E, Rubio P, Sobrino R, Esparza A, Gil M, et al. [Periodical EEG pattern modifications in herpetic encephalitis treated with acyclovir]. Rev Neurol. Jul 1996;24(131):829-32. [Medline].

  30. Mook-Kanamori B, van de Beek D, Wijdicks EF. Herpes simplex encephalitis with normal initial cerebrospinal fluid examination. J Am Geriatr Soc. Aug 2009;57(8):1514-5. [Medline].

  31. Lakeman FD, Whitley RJ. Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis. Apr 1995;171(4):857-63. [Medline].

  32. Cinque P, Cleator GM, Weber T, Monteyne P, Sindic CJ, van Loon AM. The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis. J Neurol Neurosurg Psychiatry. Oct 1996;61(4):339-45. [Medline]. [Full Text].

  33. Schloss L, Falk KI, Skoog E, Brytting M, Linde A, Aurelius E. Monitoring of herpes simplex virus DNA types 1 and 2 viral load in cerebrospinal fluid by real-time PCR in patients with herpes simplex encephalitis. J Med Virol. Aug 2009;81(8):1432-7. [Medline].

  34. Domingues RB, Lakeman FD, Mayo MS, Whitley RJ. Application of competitive PCR to cerebrospinal fluid samples from patients with herpes simplex encephalitis. J Clin Microbiol. Aug 1998;36(8):2229-34. [Medline]. [Full Text].

  35. Wildemann B, Ehrhart K, Storch-Hagenlocher B, Meyding-Lamadé U, Steinvorth S, Hacke W, et al. Quantitation of herpes simplex virus type 1 DNA in cells of cerebrospinal fluid of patients with herpes simplex virus encephalitis. Neurology. May 1997;48(5):1341-6. [Medline].

  36. Weil AA, Glaser CA, Amad Z, Forghani B. Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis. Apr 15 2002;34(8):1154-7. [Medline].

  37. Benson PC, Swadron SP. Empiric acyclovir is infrequently initiated in the emergency department to patients ultimately diagnosed with encephalitis. Ann Emerg Med. Jan 2006;47(1):100-5. [Medline].

  38. Rathmann K, Scott SA. Acyclovir. In: Drug Evaluation Monographs. Micromedex:2005.

  39. Stone KM, Reiff-Eldridge R, White AD, Cordero JF, Brown Z, Alexander ER, et al. Pregnancy outcomes following systemic prenatal acyclovir exposure: Conclusions from the international acyclovir pregnancy registry, 1984-1999. Birth Defects Res A Clin Mol Teratol. Apr 2004;70(4):201-7. [Medline].

  40. James SH, Kimberlin DW, Whitley RJ. Antiviral therapy for herpesvirus central nervous system infections: neonatal herpes simplex virus infection, herpes simplex encephalitis, and congenital cytomegalovirus infection. Antiviral Res. Sep 2009;83(3):207-13. [Medline]. [Full Text].

  41. National Institute of Allergy and Infectious Diseases. A Phase III Double-Blind, Placebo-Controlled Trial of Long Term Therapy of Herpes Simplex Encephalitis (HSE): An Evaluation of Valacyclovir (CASG-204). ClinicalTrials.gov. Available at http://clinicaltrials.gov/ct/show/NCT00031486?order=1. Accessed August 8, 2007.

  42. Glenny AM, Fernandez Mauleffinch LM, Pavitt S, Walsh T. Interventions for the prevention and treatment of herpes simplex virus in patients being treated for cancer. Cochrane Database Syst Rev. Jan 21 2009;CD006706. [Medline].

  43. Sergerie Y, Boivin G, Gosselin D, Rivest S. Delayed but not early glucocorticoid treatment protects the host during experimental herpes simplex virus encephalitis in mice. J Infect Dis. Mar 15 2007;195(6):817-25. [Medline].

  44. Thompson KA, Blessing WW, Wesselingh SL. Herpes simplex replication and dissemination is not increased by corticosteroid treatment in a rat model of focal Herpes encephalitis. J Neurovirol. Feb 2000;6(1):25-32. [Medline].

  45. Kamei S, Sekizawa T, Shiota H, Mizutani T, Itoyama Y, Takasu T, et al. Evaluation of combination therapy using aciclovir and corticosteroid in adult patients with herpes simplex virus encephalitis. J Neurol Neurosurg Psychiatry. Nov 2005;76(11):1544-9. [Medline]. [Full Text].

  46. Martinez-Torres F, Menon S, Pritsch M, Victor N, Jenetzky E, Jensen K, et al. Protocol for German trial of Acyclovir and corticosteroids in Herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial [ISRCTN45122933]. BMC Neurol. Oct 29 2008;8:40. [Medline]. [Full Text].

 
Previous
Next
 
Axial proton density-weighted image in 62-year-old woman with confusion and herpes encephalitis shows T2 hyperintensity involving right temporal lobe.
Axial gadolinium-enhanced T1-weighted image reveals enhancement of right anterior temporal lobe and parahippocampal gyrus. At right anterior temporal tip is hypointense, crescentic region surrounded by enhancement consistent with small epidural abscess.
Axial diffusion-weighted image reveals restricted diffusion in left medial temporal lobe consistent with herpes encephalitis. This patient also had positive result on polymerase chain reaction assay for herpes simplex virus, which is both sensitive and specific. In addition, patient had periodic lateralized epileptiform discharges on electroencephalography, which supports diagnosis of herpes encephalitis.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.