Diagnosing herpes in CSF

New laboratory techniques for determining herpes virus CNS infections.

The Virus

HERPES simplex virus (HSV) belongs to the α-herpesviridae subfamily of herpesviruses. 

There are two types of HSV: type 1 and type 2. HSV is an enveloped virus with an internal core (capsid) containing dsDNA. The genome of HSV-1 and HSV-2 share 50–70% homology.

Central nervous system (CNS) infections are serious complications of HSV disease, which can occur in children and adults. Immunocompromised patients and neonates experience severe symptoms with potential of disseminated infection and death. 

The viral load of HSV in cerebral spinal fluid (CSF) is low compared to other clinical specimens. Culture for HSV is therefore difficult, as this technique is not very sensitive. HSV PCR is now recognised as the reference standard, given its high sensitivity and specificity. The determination of HSV DNA in CSF has been markedly enhanced with the availability of commercial kits for real-time PCR which significantly reduces turn-around time to results. 

Molecular diagnostic testing for infectious diseases is particularly useful for organisms that are difficult or slow to grow in the laboratory. When a causative agent is found, HSV and enterovirus are the most commonly identified viral pathogens. Prompt diagnosis of HSV encephalitis is especially important because treatment with intravenous acyclovir decreases morbidity and mortality. 

Furthermore, a rapid diagnosis of enteroviral meningitis can facilitate early discharge from hospital and prevent unnecessary antibiotic treatment and further laboratory testing. 

The majority of viral PCR tests performed on CSF, however, yield negative results, and the aetiology of aseptic meningoencephalitis remains unknown more than half the time. 

Perhaps this is due to the rise in the number of PCR tests ordered as part of the diagnostic evaluation of suspected CNS infection, even when there is a low likelihood of a viral cause.

Herpes simplex virus type 2 (HSV-2) infections may give rise to symptoms on the skin and mucous membranes and in the nervous system. Neurological complications appear with or without mucocutaneous lesions. After the primary infection, the virus remains latent in the dorsal root ganglia, where it can reactivate. HSV-2 meningitis carries a considerable risk of future neurological morbidity and is the major cause of recurrent aseptic meningitis. Aseptic meningitis and meningoencephalitis may also be caused by varicella-zoster virus infection, frequently without the zoster rash. 

A published retrospective study showed that during the year following the acute phase of HSV-2 meningitis, more than 30% of 40 patients suffered from recurrent neurological symptoms (one or several episodes of recurrent meningitis or myelitis or distinct attacks of severe headache). With confirmed HSV-2 laboratory diagnosis, accurate information about diagnosis, prognosis and treatment options – i.e. early episodic treatment or suppressive prophylaxis in cases with frequent recurrences – is possible. 

Isolation of HSV from CSF has been reported in cases of primary meningitis caused by both types of virus, i.e. HSV-1 and HSV-2. 

In recurrent meningitis, attempts to isolate HSV in the CSF have been unsuccessful. The implementation of PCR for the detection of viral DNA in CSF has resulted in considerable improvement. HSV DNA has been detected by PCR in several patients with primary as well as recurrent aseptic meningitis, both with and without mucocutaneous lesions. 

SUMMARY

Real-time PCR for the detection of HSV DNA in CSF is a quick and efficient tool for the aetiological diagnosis of aseptic meningitis and should be used first line in routine diagnosis. 

With doctors’ increased awareness of the diagnosis, a thorough history taking and the consistent use of novel diagnostic methods, HSV aetiologies will be revealed in an even higher percentage of cases. 

References

1. E.Franzen-Rohl et al. 2007. Increased detection rate in diagnosis of Herpes Simplex Virus type 2 meningitis by real-time PCR using Cerebrospinal Fluid Samples. Journal of Clinical Microbiology. p.2516-2520.

2. K.E.Hanson et al. 2007. Validation of laboratory screening criteria for Herpes Simplex Virus testing of Cerebrospinal Fluid. Journal of Clinical Microbiology. p. 721-724.

Dr Bernie Hudson MBBS, DTPH, FACTM, FAFPHM, FRACP, FRCPA

Dr Hudson is a clinical microbiologist and infectious diseases physician

Co-author: Tom Karagiannis, Senior hospital scientist, Microbiology Department, Pacific Laboratory Medicine Services (PaLMS)