Version May 2024
INTRODUCTION — Although encephalitis is a rare complication of herpes simplex virus (HSV) infection, HSV is the most common cause of nonepidemic, sporadic, acute focal encephalitis in the United States [1,2]. The estimated frequency of HSV encephalitis (HSE) is between 1:250,000 and 1:500,000 persons per year [1]. The administration of acyclovir reduces the mortality from approximately 70 percent in untreated infection to 19 to 28 percent; however, neurologic impairment is common (44 to 62 percent) in those who survive [3,4]. (See "Herpes simplex virus type 1 encephalitis", section on 'Treatment'.)
Given the severity of the illness and the availability of effective therapy, there is a need for a rapid and accurate diagnostic test for HSV encephalitis (HSE). In adults, the infection is usually caused by HSV type 1 and may be due to primary infection or reactivation of latent infection. (See "Herpes simplex virus type 1 encephalitis".)
Neonatal HSV infection occurs in 1:3500 to 1:5000 deliveries in the United States [2]. It is usually acquired by intrapartum contact with infected maternal genital secretions, and is therefore most often due to HSV type 2. There are three general presentations of the disease: skin, eye, and mouth (45 percent); encephalitis (35 percent); and disseminated disease (20 percent), which is often associated with central nervous system (CNS) involvement. Thus, CNS disease occurs in approximately 50 percent of babies with neonatal HSV infection.
STANDARD DIAGNOSTIC METHODS — The clinical presentation does not distinguish herpes simplex encephalitis (HSE) from encephalitis caused by other viruses such as St. Louis (flavivirus), Eastern equine (togavirus), and Epstein-Barr virus (EBV), or from Mycobacterium tuberculosis meningitis [5]. (See "Viral encephalitis in adults" and "St. Louis encephalitis".)
Culture of herpes simplex virus (HSV) from the cerebrospinal fluid (CSF) of adults with HSE has a sensitivity of less than 10 percent. Better results are obtained with tests that measure HSV antigens or antibodies in the CSF; these tests are associated with sensitivity and specificity rates of 75 to 85 percent and 60 to 90 percent, respectively [2].
The "gold standard" for the diagnosis of HSE has been brain biopsy, with identification of HSV in the tissue by cell culture or immunohistochemical staining. Although brain biopsy has a sensitivity of 99 percent and a specificity of 100 percent [2], it requires an invasive procedure, and the results may not be available for several days. (See "Herpes simplex virus type 1 encephalitis".)
Because of these limitations, CSF polymerase chain reaction (PCR) testing has been evaluated as a diagnostic test for HSE. It is rapid and associated with a very high sensitivity and specificity. (See 'Polymerase chain reaction testing' below.)
There are several tests that have been approved for use with genital specimens; these tests should not be used for testing CSF. The concentration of HSV DNA in genital infections may be much greater than that seen for a CNS infection, so a test designed to detect HSV in genital specimens may not have adequate sensitivity for CSF specimens. Moreover, these tests have not been validated with CSF specimens.
POLYMERASE CHAIN REACTION TESTING — Two large studies compared cerebrospinal fluid (CSF) polymerase chain reaction (PCR) testing to either brain biopsy [6,7] or intrathecal herpes simplex virus (HSV) antibody production [6] in patients with suspected herpes simplex encephalitis (HSE).
●In the first study, 42 of 43 patients with biopsy-proven HSV encephalitis had CSF positive for HSV-1 DNA by PCR (all but one on the first CSF sample), while the CSF from 60 patients with non-HSV acute febrile focal encephalopathy were negative [6]. The one false negative test occurred in a patient who had been treated with acyclovir. PCR remained positive for as long as 27 days after the onset of symptoms.
●The second study compared PCR to brain biopsy in specimens from both HSV culture-positive and negative specimens [7]. HSV DNA was detected in the CSF in 53 of 54 patients (98 percent) with biopsy-proven HSV encephalitis compared with 3 of 47 patients (6 percent) whose brain tissue was culture-negative. Sensitivity was 98 percent and specificity was 94 percent. The three presumptive false-positive tests occurred when the site of the brain disease was not properly sampled or the brain tissue was not properly cultured; thus, the specificity of HSV PCR may approach 100 percent for the diagnosis of HSE. The sensitivity of the PCR assay was not significantly decreased until after the patient received greater than seven days of therapy [7].
PCR is positive early in the course of the illness (within the first 24 hours of onset of symptoms) and remains positive during the first week of therapy [8]. In some cases, viral genomes persist in the CSF for two weeks or longer after the onset of antiviral therapy [7,8].
PCR is also useful for the diagnosis of neonatal HSV infection. In one series, HSV DNA was detected in the CSF in 26 of 34 (76 percent) infants with CNS disease, 13 of 14 (94 percent) with disseminated infection, and 7 of 29 (24 percent) with skin, eye, or mouth involvement [9]. One of the seven patients in the last group subsequently developed severe neurologic impairment.
Based upon these results, detection of HSV DNA in CSF by PCR has become the standard for the diagnosis of HSE and neonatal HSV infection involving the CNS. The primer pairs used in these studies identified HSV types 1 and 2 and did not cross react with other herpesviruses including cytomegalovirus (CMV), varicella-zoster virus (VZV), human herpesvirus-6, and EBV.
The persistence of HSV DNA in the CSF of newborns for greater than one week after initiating therapy is associated with a poor outcome [10].
Specimen collection — Most HSV PCR assays require between 0.5 and 1 mL of CSF. An evaluation of the stability of HSV DNA in CSF containing lymphocytes and monocytes revealed little degradation of HSV DNA in specimens that were stored for 30 days at room temperature (20 to 23ºC), refrigerated (2 to 8ºC), or frozen (-20 to -70ºC) [11]. Specimens can be transported at room temperature, although refrigeration or freezing may be recommended by reference laboratories. Specimens are stored refrigerated or frozen until the testing is performed. Testing should not be done on the supernatant fraction (cell free) of the CSF that has been centrifuged as the sensitivity could be decreased since cell-associated virus is removed from the sample.
Interpretation of the results — HSV PCR results should be interpreted cautiously since neither the sensitivity nor specificity of the test is 100 percent. The test results should always be interpreted within the context of the clinical presentation of the patient. If testing results do not correlate with the clinical impression, repeat testing should be performed. As noted above, the sensitivity of the HSV PCR assay is not significantly decreased until after seven days of therapy.
False-negative HSV PCR results may be due to low sensitivity of a particular assay. There is no standardized assay; rather most laboratories develop their own "laboratory-developed tests." As a result, assay sensitivity may vary among laboratories. The presence of substances in the CSF that inhibit amplification (eg, blood) may also lead to false negative results. Thus, the assay should include a method to remove inhibitory substances from the CSF specimen or include an inhibition control for each specimen.
One study found that neurologic disease with HSV is rarely seen in individuals with a normal CSF white blood cell count and protein concentration [12], although caution should be exercised in applying this generalization to immunocompromised patients as they may not mount a typical inflammatory response to HSV infection. A subsequent study validated that restricting HSV testing to samples that met criteria based upon CSF values (white blood cell count of >5 cells/mm3 or protein level >50 mg/dL) or host criteria (age <2 years, HIV infection, or history of transplantation) was cost effective and did not result in any missed HSV diagnoses [13]. In this study, two of the rejected specimens tested positive for HSV-2 DNA; however, both met acceptance criteria that had not been communicated to the laboratory. A decision analysis also found that adopting these screening criteria was cost effective when less than 1 in 200 patients deferred from testing had an HSV CNS infection, but patients with age <2 years, HIV infection, or history of transplantation were excluded from the analysis [14].
False-positive HSV PCR results are most commonly due to contamination from carryover of amplified product or cross-contamination during specimen processing. Laboratories performing PCR should follow strict methods to minimize this risk. The widespread use of real-time PCR testing has greatly reduced the risk of contamination due to carryover of amplified product. In addition, care must be taken to avoid cross contamination during specimen handling and processing when testing both genital and CSF specimens for HSV DNA using PCR. Some laboratories address this by processing and testing genital and CSF specimens separately.
Availability of the test — The Simplexa HSV 1 & 2 Direct kit (Focus Diagnostics and Diasorin Molecular), a real-time PCR assay for the detection and differentiation of HSV 1 & 2 DNA from CSF, has been cleared by the United States Food and Drug Administration (FDA) to aid in the diagnosis of HSV-1 and HSV-2 infections of the CNS. The FilmArray Meningitis/Encephalitis Panel (BioFire Diagnostics), which has also been cleared by the FDA, is a highly multiplexed test that detects 14 pathogens, including bacteria, viruses, and cryptococcus in CSF specimens from patients with suspected CNS infections. HSV-1 and HSV-2 are included in the panel; the sensitivity and specificity of the test for the detection of HSV-1 and HSV-2 DNA compares very well to laboratory-developed PCR assays [15,16].
However, many laboratories continue to use tests that they developed themselves. Thus, clinicians should inquire about assay sensitivity, specificity, and the use of inhibition controls when a reference laboratory uses such laboratory developed PCR assays. In addition, they should ensure that testing is performed using a primer pair that detects HSV types 1 and 2 with equal sensitivity.
HSV MENINGITIS — HSV can cause aseptic meningitis, usually a self-limited disease that resolves without specific therapy; in a small subset of patients HSV can lead to recurrent lymphocytic meningitis over a period of many years [2,17]. In adults, HSV-associated meningitis is usually caused by HSV type 2 [2,17,18].
Based on data demonstrating the relative performance characteristics of PCR testing compared with brain biopsy and culture in patients with encephalitis, and other data in patients with genital ulcerative disease, PCR testing is also the preferred diagnostic test of choice in patients with suspected HSV-associated meningitis. It is estimated that CSF viral culture has a sensitivity of only 50 percent in patients with HSV meningitis. Culture-based techniques for HSV meningitis may have low sensitivity because HSV DNA levels are generally lower among patients with clinical meningitis than encephalitis [19]. The clinical diagnosis may also be somewhat elusive since many patients do not have genital lesions at the time of presentation, particularly in the setting of recurrent meningitis [20,21]. Thus, the absence of genital lesions should not deter the clinician from testing for HSV-2 infection in a patient with aseptic meningitis.
PCR testing is recommended by the Centers for Disease Control for suspected HSV meningitis [22], although data on the sensitivity and specificity of this diagnostic method in this setting are not available [20,21]. As an example, one study assessed the etiology of aseptic meningitis in 144 patients using a comprehensive diagnostic approach using cultures, serology, and PCR testing on multiples specimens (eg, blood, CSF, urine, throat) [20]. An etiologic agent was identified in 66 percent of patients; the most common pathogen was enterovirus followed by HSV-2, as detected by PCR. However, none of these patients had confirmation of their diagnosis through culture, blood serologies, or detection of intrathecal antibody production; there were also no data on the clinical presentation. Thus, the sensitivity and specificity of PCR cannot be inferred from these data.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infectious encephalitis".)
SUMMARY AND RECOMMENDATIONS
●Although encephalitis is a rare complication of herpes simplex virus (HSV) infection, HSV is the most common cause of nonepidemic, sporadic, acute focal encephalitis in the United States. (See 'Introduction' above.)
●Prior to the wide availability of molecular testing methodology, brain biopsy was considered the "gold standard" for the diagnosis of herpes simplex virus encephalitis; HSV was identified in tissue by cell culture or immunohistochemical staining. Although brain biopsy has a sensitivity of 99 percent and a specificity of 100 percent, it remains an invasive procedure and the results may not be available for several days. Culture and serologic techniques are not good alternatives because they have lower sensitivity and specificity than brain biopsy. (See 'Standard diagnostic methods' above.)
●Polymerase chain reaction (PCR) testing on cerebrospinal fluid (CSF) offers rapid results with high sensitivity and specificity of 98 and 94 percent, respectively, when compared with brain biopsy specimens. Detection of HSV DNA in CSF by PCR has become the standard for the diagnosis of herpes simplex virus encephalitis in adults and neonates. (See 'Polymerase chain reaction testing' above.)
●PCR testing is positive early in the course of the illness (within the first 24 hours of onset of symptoms) and remains positive during the first week of antiviral therapy. (See 'Polymerase chain reaction testing' above.)
●Most HSV PCR assays require between 0.5 and 1 mL of CSF for HSV testing. Specimens are stored refrigerated or frozen until testing is performed. (See 'Specimen collection' above.)
●HSV PCR results should always be interpreted within the context of the clinical presentation of the patient. If testing results do not correlate with the clinical impression, repeat testing should be performed. (See 'Interpretation of the results' above.)
●HSV can also cause aseptic meningitis, a self-limited disease usually associated with HSV type 2 infection. The preferred diagnostic test for patients with suspected HSV meningitis is PCR testing on cerebral spinal fluid. (See 'HSV meningitis' above.)
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