Clinicians frequently face diagnostic challenges when herpes simplex virus (HSV) is part of the list of differentials. Unfortunately, ocular HSV infections are often not diagnosed in a timely fashion, initially presenting as blepharitis or conjunctivitis. To add to the confusion, although the majority of HSV infections are unilateral, a significant number can be bilateral. Clinicians will commonly look at an array of corneal signs—or even keratouveitis—wondering if it might be HSV. 

A Deceptive Virus

Of course, there are classic features such as corneal dendrites (ulcerative) that make the diagnosis easy, but even then, other branching lesions, “pseudodendrites,” will represent a different disease anomaly. The differential is long and includes the nonulcerative dendritiform with a wide range of etiologies, such as Acanthamoeba keratitis, healing abrasions, and herpes zoster keratitis, to name a few.1

Many have nicknamed HSV the “great masquerader” for good reason. This virus can present and actually linger with many different clinical presentations well beyond the classic dendrite. For example, a simple cluster of punctate staining can desquamate down to form a dendrite later. Also, note that an anterior chamber reaction with an uncharacteristically high intraocular pressure is often HSV in disguise. The sage clinician will always say, “if I don’t know what that might be with the slit lamp, it’s commonly HSV.”

A Useful Test

Does HSV serology make sense? A quick review of what serology tells us about this patient is in order. Remember the time required for the development of IgG antibodies for HSV exposures/infections will range from three to six weeks and up to several months if antiviral medications have been used.2 So, nonreactive IgG levels do not always indicate the absence of infection. 

However, most patients have detectable IgG antibodies after exposure in three to four weeks. But, once established, life-long detection of IgG is likely forever.2 IgM antibody detection is generally considered detectable around 10 days after recent exposure and will only last for one to two weeks signifying current exposure.2,3

Contrary to popular belief, positive serology for HSV1 and/or HSV2 does not exceed more than 60% in most population-based studies in the United States. In a recent study, seroprevalence was 42.6% (HSV-1) and 18.5% (HSV-2).4 This finding means that, if a clinician does not detect IgG/IgM antibodies with appropriate timing, the chance that they are dealing with a HSV infections is virtually zero! 

Serology with IgG detection won’t guarantee a definitive diagnosis since many patients have positive antibodies to HSV-1 and/or HSV-2 due to past exposure(s). But, knowing what it isn’t (in this case, a negative serology if performed properly) can be valuable in managing vexing presentations. Although a HSV diagnosis is most often made clinically, laboratory testing is available for confirmation using cytology, cell cultures and polymerase chain reaction testing, the “gold standard,” to confirm a diagnosis. 

Commercial type-specific enzyme-linked assays are currently available to detect antibodies for HSV exposures.3 They have relatively good sensitivity for both HSV-1 and HSV-2. Please take note of the caveats listed above, specifically not relying on IgG positivity to pinpoint current exposure or infection (the patient might have life-long IgG levels without current infection). Additionally, assays may have indeterminant levels of antibody with borderline reactivity or equivocal findings.

Our practice uses this rather inexpensive testing since it is widely available and useful in the clinic for suspected HSV. It helps in the differential especially when there is an atypical or chronic presentations. Negative serology will allow for avoidance of unnecessary antiviral medication and direct the clinician to another etiology.

1. Rapuano C, Shovlin J. Herpes simplex virus dendritic epithelial keratitis. Accessed October 15, 2022.  

2. Herpes simplex—immunity serology. Public Health Ontario. Updated October 7, 2020. Accessed October 15, 2022.

3. Corey L, Spear PG: Infections with herpes simplex viruses. N Engl J Med. 1986;314:686-91.

4. Wang J, Cherlan DG, Goshe JM. Utility of HSV serology for chronic corneal pathology. Eye Contact Lens. 2020;46(3):190-3.