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Diagnosing and Treating Recurrent Herpes Simplex Meningitis

Diagnosing and treating quickly is crucial, since the disease can be fatal.

A 21 year-old woman presented to the emergency department (ED) with complaints of fever, headache, nausea and neck pain that started on the previous day. Vital signs included a temperature of 100.7? F, blood pressure of 99/66 mmHg, and a heart rate of 90 bpm. Ten days earlier, her routine gynecological testing was positive for Chlamydia trachomatis and herpes simplex virus type 2 (HSV-2), which was treated with a one-time oral 2-gram dose of azithromycin and a 10-day course of oral famciclovir 500 mg three times a day. No herpetic lesions were visible on physical exam in the ED. Recent testing for human immunodeficiency virus (HIV) was negative.

In the ED, empiric ceftriaxone was initiated for presumed bacterial encephalopathy or meningitis. A complete blood count (CBC) revealed a normal white blood cell count (WBC) of 9.3 x 103 / mm3. A lumbar puncture was performed, and evaluation of cerebrospinal fluid (CSF) revealed a slightly elevated WBC level of 8.23 x 103 /mm3 (reference range: 0-5 cells/mm3) with 81% lymphocytes and an elevated protein of 98 mg/dL (reference range: 15-60 mg/dL). No organisms were detected on gram stain or culture, but HSV-2 was identified in her CSF by polymerase chain reaction (PCR) (see Table 1, LP1, below). Ceftriaxone was discontinued, and intravenous (IV) acyclovir was started. Three days later, the patient was discharged with a 2-week course of oral valacyclovir 1,000 mg three times daily.

Repeated ED Visits
The patient returned 2 days later with symptoms of worsening positional headache, back pain, nausea, and new-onset photophobia. She was afebrile, and a CBC again demonstrated a normal WBC count. Notably, meningeal signs were absent. Post-lumbar puncture headache was suspected, and intravenous caffeine provided adequate relief. Intravenous acyclovir 700 mg three times a day was resumed during her 3-day hospital stay. There was no consultation with infectious disease or neurology during this hospitalization. The patient was discharged with arrangements for a 10-day outpatient course of IV acyclovir 700 mg three times a day.

Four days after discharge, the patient returned to the ED with severe nausea, vomiting, headache and a serum creatinine level of 2.5 mg/dL (reference range: 0.5-1.5 mg/dL). This was attributed to an intolerance of the high-dose acyclovir, with the development of dehydration and acute kidney injury. Renal function improved, and her creatinine returned to baseline of 0.9 mg/dL within 1 month of cessation of acyclovir and introduction of prochlorperazine and supportive fluids.

After 17 days at home, the patient presented to her primary care provider with herpetic genital lesions. She was prescribed oral acyclovir 200 mg every 4 hours and continued the regimen for 5 days until severe headaches and neck stiffness developed. Lumbar puncture demonstrated increased WBC count and lymphocytes with negative PCR for HSV 1 and 2 (see Table 1, LP2, below). The patient refused admission to the hospital and returned home with a new regimen of oral acyclovir 400 mg every 4 hours.

Three days later, the patient again presented with meningeal signs and was admitted for a third time. No genital lesions were observed. After a telephone consultation with an infectious disease physician, acyclovir was discontinued, and the patient began a regimen of oral famciclovir 500 mg three times daily that resulted in marked symptomatic improvement. The patient followed up as an outpatient with the infectious disease physician and was instructed to continue this new regimen indefinitely as maintenance therapy.

Ongoing Care
The patient followed up with her infectious disease physician several months after her last hospitalization to discuss continued suppression. Due to the cost of famciclovir, she requested to discontinue it and substitute oral acyclovir 400 mg twice a day. Within 4 weeks, the patient suffered an outbreak of genital lesions and resumed her previous regimen of oral famciclovir 500 mg three times a day.

After 1 year without recurrence of genital lesions, neurological signs or meningismus, the patient elected to reduce her famciclovir dose to 500 mg twice daily. After success of the new regimen, the patient further reduced famciclovir to 500 mg once daily. She has tolerated this treatment well for approximately 4 years but reports rare minor genital herpes outbreaks accompanied by low-grade fever, headache and neck stiffness. When this occurs, the patient increases her dose of famciclovir to 500 mg three times a day until the symptoms subside. She has not required further medical attention during these outbreaks and has avoided additional hospitalizations.

SEE ALSO: Potential Complications of Herpes Zoster

Discussion
Primary genital herpes simplex virus infections are commonly associated with systemic symptoms including fever, malaise, myalgias and headache, indicating that some degree of viremia frequently occurs during primary HSV infections.1 HSV-1 infection of the central nervous system (CNS) generally presents as encephalitis, whereas HSV-2 infection of the CNS typically manifests as brainstem encephalitis, myelitis, or meningitis.2


HSV-2 meningitis is recurrent in 20% to 50% of patients. It is to be distinguished from Mollaret's meningitis, a syndrome characterized by recurrent episodes of idiopathic aseptic meningitis separated by symptom-free periods ranging from months to years.3,4

As with genital HSV, no cure for HSV meningitis exists-despite the availability of multiple antiviral therapies. Initial genital infection with HSV-2 can introduce the virus into the CSF through neural penetration into the dorsal root ganglia, where the virus then becomes dormant in the cell bodies of neurons.1 This retrograde seeding can later result in recurring meningitis, just as dormant varicella virus can reactivate and cause herpes zoster. 

The symptomatic presentation of acute aseptic (i.e., viral) meningitis closely resembles that of acute bacterial meningitis.5 It is critically important to make the correct diagnosis and initiate appropriate treatment quickly, since the disease can be fatal if not treated in a timely manner. In the typical CSF analysis of bacterial meningitis, the WBC count is elevated, neutrophils predominate, glucose is low, and protein is elevated. In CSF analysis of aseptic or viral meningitis, the WBC count is normal to slightly increased, lymphocytes predominate, and glucose and protein levels are either normal or slightly elevated (see Table 2, below).6

In this patient, the initial CSF analysis was most consistent with a viral etiology, but PCR analysis was essential in diagnosing HSV meningitis. The negative PCR result obtained following the second LP is consistent with other reports of recurrent HSV meningitis, in which identification of the virus is the exception rather than the rule.4 Ongoing antiviral therapy may also have contributed to this negative result. Overall, the predominant lymphocytes and previously positive PCR for HSV-2 strongly supported a diagnosis of recurrent HSV meningitis.

Herpes simplex encephalitis (HSE) is an important complication of HSV infection of the CNS. Without antiviral therapy, mortality rates of HSE are near 70%, and only a minority of survivors return to full function.4 Manifestations of HSE include fever, hemiparesis, ataxia, dysphasia, and seizures. 7

Early diagnosis with PCR and aggressive antiviral therapy are crucial in decreasing the severity of acute presentations of HSV-2 meningitis, preventing progression to HSE, and reducing the probability of recurrence.8 Intravenous acyclovir should be used empirically in any patient who presents with meningoencephalitis or severe disease. Appropriate oral antiviral therapy should be prescribed to those with other symptoms of HSV infection such as genital lesions or cold sores. Treatment should not be withheld while waiting for definitive CSF PCR identifying HSV.9

Viral Resistance
The patient in this case report was diagnosed with recurrent HSV meningitis, but treatment with acyclovir yielded only transient and incomplete relief. Therefore, viral resistance to the drug must be considered. Both acyclovir and famciclovir are phosphorylated by herpesvirus thymidine kinase (TK), and the resulting molecule disrupts function of the viral DNA polymerase. This prevents DNA synthesis and therefore viral replication ceases.8

The most common mode of viral resistance to acyclovir is by absent or decreased production of viral TK. These resistant viruses are found primarily in immunosuppressed patients who have been on long-term antiviral prophylactic therapy with acyclovir.8 HSV isolates from immunocompetent patients demonstrate acyclovir resistance in approximately 0.3% of cases. Acyclovir resistance in vitro strongly predicts HSV resistance to famciclovir; however, partial alteration of viral TK or mutation of viral DNA polymerase may still permit famciclovir sensitivity.11 While this may explain the positive outcome in this case, her response may also have been due to famciclovir's increased bioavalability (77% vs 21.5% for acyclovir) or longer intracellular half-life (approximately 10 hours vs. 2 to 4 hours for acyclovir) compared to acyclovir. 12,13

In cases of apparent acyclovir resistance, additional treatment options for HSV-2 must be considered. Cidofovir and foscarnet function independently of viral TK and have shown efficacy against acyclovir-resistant HSV-2.8 The increased risks associated with these drugs, especially nephrotoxicity, are significant but acceptable given the potentially catastrophic outcomes seen with HSE. Therefore, initial therapy with one of these drugs likely would have been preferred, with eventual suppressive therapy with famciclovir or another drug with activity against HSV like valganciclovir. Acyclovir remains the first-line therapy of choice (due to efficacy and cost) for HSV-2 outbreaks, including both CNS and mucocutaneous involvement. However, when a patient's symptoms do not abate with administration of acyclovir, famciclovir may be initiated, with consideration of cidofovir or foscarnet if disease is severe or persistent. Patients with recurrent disease should continue oral antiviral suppression during times of remission and have regular follow-up evaluations.

Lydia Novruzov is a physician assistant specializing in hematology and oncology in Abingdon, VA. Sarah Hogue is a physician assistant specializing in cardiothoracic surgery in Mishawaka, Indiana. Brianne Wagenman is a physician assistant specializing in pediatric dermatology in San Diego, CA. Christopher Roman is an assistant professor and assessment chair in the physician assistant program at Butler University in Indianapolis.

References

1.    Johnston C, et al. Herpes simplex virus viremia during primary genital infection. J Infect Dis. 2008;198(1):31-34.

2.    Omland LH, et al. Herpes simplex virus type 2 infections of the central nervous system: A retrospective study of 49 patients. Scand J Infect Dis. 2008;40(1):59-62.

3.    Jensenius M, et al. Herpes simplex virus type 2 DNA detected in cerebrospinal fluid of 9 patients with Mollaret's meningitis. Acta Neurol Scand. 1998;98(3):209-212.

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

5.    Franzen-Rohl E, et al. High diagnostic yield by CSF-PCR for entero- and herpes simplex viruses and TBEV serology in adults with acute aseptic meningitis in Stockholm. Scand J Infect Dis. 2008; 40(11-12):914-921.

6.    Harrell T, Hammes JS. Meningitis Admitted to a Military Hospital: A Retrospective Case Series. Mil Med. 2012;177(10):1223-1226.

7.    Levitz RE. Herpes simplex encephalitis: a review. Heart Lung.1998;27(3):209-212.

8.    Kimberlin DW, Whitley RJ. Antiviral therapy of HSV-1 and -2. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al., ed. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007;Chapter 64.

9.    Chadwick DR. Viral meningitis. Br Med Bull. 2005;75-76(1):1-14.

10.  Bacon TH, et al. Herpes simplex virus resistance to acyclovir and penciclovir after two decades of antiviral therapy. Clin Microbiol Rev. 2003;16(1):114-128.

11.  Kimberlin DW, et al. Molecular mechanisms of antiviral resistance. Antiviral Res. 1995;26:369-401.

12.  Crumpacker C. The pharmacological profile of famciclovir. Semin Dermatol. 1996;15(2 Suppl 1):14-26.

13.  Steingrimsdottir H, et al. Bioavailability of aciclovir after oral administration of aciclovr and its prodrug valaciclovir to patients with leukopenia after chemotherapy. Antimicrob Agents Chemother. 2000;44(1):207-209.

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