Herpes simplex type-2 recurrent meningitis: Mollaret or not Mollaret?

Dear Editor:

With respect to the very lucid editorial of J. A. Oteo about Acute Aseptic Meningitis,¹ we would like to expose our opinion about the most appropriate terminology to correctly denominate infectious diseases. Recurrent meningitis (RM) is a rare condition (classically known as Mollaret's syndrome)² defined by two or more episodes of lymphocytic meningitis lasting two to five days.³ It usually occurs during several years with spontaneous and complete recovery between each episode. Cerebrospinal fluid (CSF) analysis typically shows pleocytosis (an increase of mononuclear cells known as ‘ghost cells’, or Mollaret's cells), increased protein and normal glucose. In 1982, herpes simplex virus type 1 (HSV-1) was isolated in a patient with Mollaret's meningitis.⁴ This was confirmed nine years after⁵; however, HSV-2 is now the most frequent viral etiology associated.⁶ Mollaret's meningitis has been linked to infections, autoimmune diseases, medications, and intracranial tumors. We report here an infrequent experience with a woman diagnosed of ten episodes of meningitis in the last twenty-five years. HSV-2 was demonstrated by CSF's Protein Chain Reaction (PCR) assay in the seventh episode.

A 30-year-old Caucasian woman was admitted in our service for acute recurrent meningitis. From 1994 to 2006 she had suffered six more episodes of meningitis every 2–3 years. She was diagnosed of Mollaret's syndrome in her reference hospital. In September 2006, she was admitted, for the first time, at the Infectious Diseases Unit due to fever, headache, malaise and meningismus (the seventh episode of RM). The CSF study showed: 165 leucocytes (95% MNCs, with no Mollaret's cells), increased proteins (103 mg/dl), and normal glucose. CSF serology was negative (RPR, Brucella spp., Chlamydia pneumoniae, Coxiella burnetii, Mycoplasma pneumoniae, Treponema pallidum, Borrelia burgdorferi, Leptospira spp., HIV, CMV, EBV, Coxsackie's A9/B, Echo virus, and HSV-1). Serum HSV-2 antibodies (IgG) were positive. PCR assay in CSF for mycobacteria, enterovirus, VHS-6, CMV, EBV and VVZ was negative, but it was positive for HSV-2. Brain CT scan and RNM were both normal. Serum autoantibodies were negative. Immunologic study was normal. The Mantoux test was negative. She was treated with IV acyclovir (200 mg/day/7 days) with a good clinical and CSF response. In November 2006, oral famciclovir (750 mg/day) was prescribed as prophylaxis. One week later, she discontinued the medication for economical reasons. So, it was switched to oral acyclovir (400 mg/bid). After 12 months without meningitis, acyclovir was suppressed in November 2007. In January and August 2008, there were two news episodes. She was treated in her reference hospital with IV acyclovir (doses unknown) with no anti-herpes prophylaxis. In March 2009, she was newly admitted at the Infectious Diseases Unit because of the tenth episode. CSF study revealed 125 leucocytes (95% MNCs), elevated protein (117 mg/dl) and normal glucose. PCR study of CSF was negative for various viruses including HSV-1 and 2. Nevertheless, she received IV acyclovir during 10 days with normalization of the CSF anomalies. She was put on oral acyclovir (400 mg/bid); however, the prophylaxis was discontinued by herself one year later (April 2011) because she wanted to be pregnant. After 16 months of follow-up, she is asymptomatic. In total, the patient has suffered ten episodes of meningitis during 19 years.

In 1944, Mollaret described for the first time a syndrome of RM associated with CSF mononuclear pleocytosis, elevated protein level, and followed by spontaneous resolution.² This syndrome encompasses a heterogeneous group of causes, but the most common is HSV-2 infection.^6–8 The prevalence is 1–2.2 cases/100,000 populations.⁶ Total episodes may reach 30 or more. The median time interval between each one episode is 47 months (range: 1–216 months).⁶ The typical patient is a middle-aged immunocompetent woman. Up to 40% of the patients reported a history of genital herpes.⁸ RM syndrome can manifest as meningitis alone, or it can also develop some neuropsychological symptoms.^6,8 The acute crisis normally disappears after 3–5 years, although some can last over 28 years.⁸ The recurrence rate is usually 5.6%,⁶ and total recovery is the rule. The diagnosis of HSV-2 RM is usually based on the typical CSF pattern plus the acute and convalescence serologic demonstration of anti-HSV IgM/IgG antibodies in CSF. But, at present, it is mandatory to seek HSV-2 DNA by PCR (Nested-PCR or real-time PCR).^8,9 Optimal timing to show the most positive-PCR samples is 2–5 days after the onset of acute symptoms.⁶ A lower viral load, or an earlier timing of the CSF samples, could originate false-negative results. Cell culture of HSV can be positive up to 72% of patients in the first episode, but it is usually negative in the recurrences.¹⁰ Therapy of recurrent meningitis requires the treatment of every specific etiology. In this sense, intravenous acyclovir (at less, during 7 days) is the most common option for HSV recurrent meningitis.

Our patient is a paradigmatic model of recurrent meningitis properly diagnosed as herpes simplex type-2 recurrent meningitis. Like other meningitis caused by different etiologies, this is generally known in the international literature as Mollaret's syndrome. Nowadays, the genomic era allows a strict specific etiological diagnosis. So, we support the use of Mollaret as eponym only when there is not an obvious etiology of recurrent meningitis after a detailed clinical and laboratory study.^7,8