Recurrent Benign Lymphocytic Meningitis Due to HSV-2: A Case Report

Recurrent benign lymphocytic meningitis (RBLM) is an uncommon form of aseptic meningitis characterized by the recurrence of meningeal symptoms followed by spontaneous recovery. Historically, RBLM has been attributed to herpes simplex virus (HSV) type 2 infection. Diagnosis is traditionally confirmed by PCR of viral DNA isolated from the CSF. Although the disease course is usually benign, antiviral therapy may benefit some patients. Here, we report the case of a young woman diagnosed with four episodes of aseptic meningitis within 10 years. The presence of HSV type 2 in the CSF was confirmed using PCR in three of the episodes. After the resolution of acute attacks, the patient was symptom-free with no neurological sequelae.


Introduction
Recurrent benign lymphocytic meningitis (RBLM) is a rare condition defined as three or more episodes of aseptic meningitis with complete recovery between each episode [1].Some reports have defined this syndrome as Mollaret's meningitis, whereas others have restricted the definition of Mollaret's meningitis to recurrent aseptic meningitis of unknown cause [2,3], according to Bruyn's criteria [4].
Similarly to meningitis caused by other infections, symptoms of RBLM include headache, fever, stiff neck, and photophobia.HSV type 2 (HSV-2) has been well established as the most common causative agent [5].The clinical presentation and results of basic cerebrospinal fluid (CSF) studies (cell count, protein, and glucose) strongly suggest an underlying viral cause of meningitis.However, the definitive diagnosis is based on polymerase chain reaction (PCR) testing of the CSF.Although the course of the disease is self-limiting, antiviral treatment may be beneficial [6].

Case Presentation
Here, we present the case of a 46-year-old woman with a known history of hypertension, who was receiving medical treatment.She presented to the emergency department (ED) in May 2022, with a 3-day history of headache and stiff neck.She reported having experienced three similar episodes with the same symptoms between 2011 and 2015.At that time, she was diagnosed with aseptic meningitis, and PCR confirmed the presence of HSV-2 in two of three previous CSF samples.
At presentation to the ED, she was hemodynamically stable and afebrile, and was not experiencing respiratory distress.A physical examination revealed neck stiffness.The results of her chest, abdominal, and skin examinations were unremarkable.
Findings of basic laboratory blood tests-including complete blood count, renal function tests, and liver function tests-were all within normal limits.Because of her clinical presentation, physical examination findings, and history of multiple meningitis episodes, a lumbar puncture was planned after brain imaging.An MRI brain scan was performed during her stay in the ED and did not show any findings suggestive of ischemia, hemorrhage, brain-occupying lesions, or signs of increased intracranial pressure.Lumbar puncture was subsequently performed.CSF fluid analysis showed an elevated white blood cell (WBC) cell count of 295 cells/μl, with a mononuclear predominance (99%).Her protein level was elevated, at 1232 mg /L (reference range 150-450 mg/L), and her glucose level was low, at 2.07 mmol/L (reference range 2.22-3.89mmol/L).
During hospitalization, CSF culture and Gram staining were negative for bacterial growth.However, PCR testing of the CSF viral panel was positive for HSV-2.
After the culture results were obtained, the empirically started antibiotics were discontinued.However, the antiviral drug acyclovir was administered for 7 days.The patient's condition improved, and her symptoms resolved completely within 5 days.Table 1 shows the results of CSF analysis and PCR for the viral panel.

Discussion and Conclusion
RBLM is an uncommon aseptic meningitis characterized by three or more episodes of meningeal symptoms lasting for 2-5 days, followed by complete spontaneous resolution [1,2,5].It is typically associated with viral infection [3], autoimmune diseases [6], drugs, and tumors.The attacks have been described to occur over a period of weeks to years [3].Typically, affected patients present with classical symptoms of meningitis, such as fever, headache, photophobia, and neck stiffness.Females are most commonly affected [6].
A study by Jarrin et al. has reported that 20-30% of patients have a risk of developing RBLM after initial HSV-2 meningitis [7].Interestingly, most patients with RBLM due to HSV-2 have no history of genital herpetic lesions or active lesions during an RBLM attack [8], both of which were also absent in our patient.
Most cases of RBLM reported in the literature have been attributed to HSV-2 infection.However, few studies have addressed the prevalence of HSV-2 infection in RBLM.A prospective cohort study by Tedder et al. enrolled 13 patients diagnosed with RBLM.HSV-2 DNA was detected in CSF samples from 10 of the 13 patients (77%) [9].Additionally, Kupila et al. have evaluated the etiology of RBLM in 14 patients through PCR analysis of CSF samples.Herpes simplex viruses 1 and 2 were associated with RBLM in 11 patients, and a predominance of HSV2 was observed [10].In another study by Kallio-Laine et al. at Helsinki University Central Hospital in Finland, among 665 patients treated for lymphocytic meningitis, the prevalence of RBLM associated with HSV2 was 2.2 cases per 100,000 population [11].
RBLM has been observed in patients with varying degrees of immunoglobulin (Ig)G immunodeficiency, particularly with low levels of IgG1, IgG2, and IgG3 [2].Moreover, RBLM has been reported by Bonnin et al. to be associated with complement factor 1 deficiency [12].Previous studies have shown that HSV2 is the leading cause of RBLM.
Fortunately, this disease is benign, and its course is selflimiting.No clear recommendations are available for the management of RBLM, and the role of antiviral therapy is not well established.However, a retrospective observational study has demonstrated the beneficial role of antiviral therapy in immunocompromised patients with HSV meningitis, by decreasing the risk of neurological sequelae.However, the results of that study suggest that supportive treatment alone is sufficient for immunocompetent patients [13].
The role of antiviral suppressive therapy in patients with primary and recurrent HSV meningitis has been evaluated in 101 patients, in a randomized controlled trial by Aurelius et al.. Half the patients received 0.5 g valacyclovir twice daily for 12 months, and the remaining received a placebo treatment.Aurelius et al. reported no difference in the recurrence of HSV meningitis between groups during the followup.However, the recurrence of genital herpetic lesions was more common in the placebo group.In contrast to the findings during the first year, the recurrence of meningitis in the second year was higher among patients who discontinued valacyclovir treatment [14].Further studies are needed to provide recommendations for the development of suppressive therapies.RBLM is a benign self-limiting disease.HSV-2 is the most commonly reported cause of recurrent benign lymphocytic meningitis.PCR of the CSF is the gold standard for diagnosis.After recurrent HSV meningitis is confirmed, antiviral treatment during an acute episode can be considered on an individual basis.
Authors' Contributions SA and MA: patient care; manuscript writing and editing.
Funding No specific funding was received for this study.