Should Mollaret's meningitis always be treated with anti-HSV therapy?

To the Editor,

We have read with interest the letter published in your journal by Muñoz-Sanz et al.¹ They described an infrequent case of recurrent aseptic meningitis treated with aciclovir IV despite the absence of a positive result of HSV-PCR in cerebrospinal fluid (CSF). The patient had a prior history of HSV-2 recurrent meningitis that resolved with antiviral treatment. In addition, while the patient was on chronic suppressive therapy she did not have any further episodes. Withdrawal of chronic therapy was followed by three new episodes of recurrent meningitis. After reinitiating therapy the patient had no further episodes. We would like to add a clinical case to illustrate the appropriateness of their practice.

A 43-year-old male was admitted to our hospital with a history of twelve-days holocranial headaches, fever, photophobia and nausea. The patient referred to have had occasional episodes of headache after sexual intercourse, irritable bowel syndrome and an episode of acute pyelonephritis. The patient sought medical attention and was started on anti-migraine drugs with no improvement being finally referred to our hospital. On physical examination he had neither neck stiffness nor focal neurological signs. Results of CT scan and MRI of the brain were both normal. The CSF white blood cell count was 428 cells/mm (94.4% mononuclear cells), glucose level was 41 mg/dl and the protein level was 101.7 mg/dl. Gram's stain of the CSF did not show microorganisms and the CSF culture was sterile. Serologic studies (HSV, CMV, VVZ and HIV) were all IgM and IgG negative and HSV, and enterovirus CSF-PCR were also negative. Antibiotics and antivirals were discontinued and a second lumbar puncture was performed 24 h after, showing persistence of pleocytosis (140 cells/mm with 92,3% mononuclear cells) increase proteins (70 mg/dl) and normal glucose level. In the following days symptoms gradually decrease and the patient was discharged home with a diagnosis of viral lymphocytic meningitis. During the 1-year follow-up after his hospital admission the patient reported 4 new episodes of fever and migraine. Analytical tests were repeated and results did not show any difference regarding prior results but a positive IgM and IgG for HSV. With the suspicion of Mollaret's meningitis a new lumbar puncture was performed and CSF was sent for pathologic examination showing the presence of large mononuclear cells of irregular nuclei consistent with Mollaret cells. The patient was treated with oral valacyclovir for 10 days. Fever subsided and headache improved. We decided to start on chronic suppressive therapy with no new episodes in the following 12 months. Subsequent serological tests showed HSV IgM negative with HSV IgG positive. The patient decided to stop valacyclovir and after 12 months follow up he had had no further episodes.

As stated by many authors, Mollaret's meningitis should only be referred to recurrent aseptic meningitis with unknown aetiology after throughout studies including molecular tehcniques.^2–4Sensu strictu our patient had a Mollaret's meningitis; the clinical picture fulfil Bruyn's criteria,⁵ HSV antibodies were detected only after several months of his first episode and HSV PCR was negative. However, symptoms and signs resolved with anti-HSV therapy suggesting a potential role of HSV in the pathogenesis of our patient's clinical picture. It could be argued that antiviral therapy and resolution of symptoms were just a casual association because of the benign nature of the disease, however the rapid improvement of symptoms after initiating therapy and the absence of further episodes makes plausible the existence of a causal relationship.

There are many case reports in the literature where patients presented with many cases of recurrent meningitis, had prolonged hospitalizations, repeated lumbar punctures and MRI or CT scans until HSV DNA is detected in CSF examination^6–8 similar to what we and Muñoz-Sanz et al. described.¹ We believe that, provided that anti-HSV therapy is generally well tolerated, with few and known side effects, it is reasonable to start a treatment course with anti-HSV therapy in patients with recurrent aseptic meningitis irrespective of the positivity of HSV-DNA test in CSF. If initiating therapy is followed by clinical improvement, chronic suppressive therapy should be offered to patients presenting with this disease because it could lead to an avoidance of hospitalization, unnecessary diagnostic tests and therefore a reduction of costs and morbidity associated with many aseptic recurrent meningitis.