HSV‑2–Associated Mollaret’s Meningitis in a Patient with History of Prior Episodes: A Case Report

Introduction

Mollaret meningitis is a rare condition characterized by recurrent, sudden-onset episodes of aseptic lymphocytic meningitis that resolve spontaneously between attacks. Since Pierre Mollaret’s initial report in 1944, it has remained generally consistent with the classic clinical picture of sudden-onset headaches, fever, and meningismus, with associated lymphocytic pleocytosis and sterile CSF cultures. HSV-2 is now recognized as the most commonly identified cause, as confirmed by PCR testing of CSF during symptomatic episodes [¹,²,³].

Definitions of Mollaret meningitis vary across studies; a cohort study reports that a minimum of two episodes of meningitis were required for diagnosis, rather than the usual three. The authors, only considering HSV-2-associated Mollaret meningitis, reported an annual incidence of 1.2 cases per 1,000,000 adults [⁴]. Recent reports across diverse populations have shown that recurrences may be sporadic or occur years apart, affecting a broader demographic range than previously appreciated, including both sexes, various age groups, and immunocompetent and immunocompromised individuals [⁵,⁶,³].

Although Mollaret meningitis is traditionally described as benign, recent reports note that some episodes may be accompanied by significant inflammatory changes, including elevated intracranial pressure [⁷,³]. In this case, we describe a patient with a history of prior two meningitis episodes who presented with headaches and photophobia and PCR-confirmed HSV-2 meningitis and a markedly elevated CSF opening pressure. This unusual but clinically important combination underscores the need for careful diagnostic evaluation and close follow-up.

Case Presentation

A 45-year-old female patient emigrated from China 10 – 15 years ago, with a past medical history of migraines, HSV-2 infection, and two self-reported prior episodes of viral meningitis (Records unavailable), presented with a mild bitemporal headache rated 4/10. The headache progressively worsened throughout the day, typically absent in the morning and intensifying at night. The pain remained localized to the temporal regions without radiation and was associated with mild nausea. She had been prescribed sumatriptan as an outpatient, but her symptoms did not improve. Several days later, on the day of presentation to the emergency department, her headache had escalated to 10/10, remained bitemporal, and was now associated with photophobia and right shoulder pain. Her immune risk evaluation was unremarkable, with negative HIV testing and no immunosuppressive conditions or medications. She was not pregnant or postpartum and denied use of corticosteroids, biologics, chemotherapy, or other immunosuppressive agents.

On arrival, vital signs included temperature 101.5°F, blood pressure 128/74 mmHg, heart rate 92 bpm, respiratory rate 18/min, and oxygen saturation 97% on room air. Given the combination of fever, severe headache, photophobia, and shoulder pain, meningitis was considered. Neurologic examination revealed the patient to be awake, alert, and oriented ×3 with intact attention, memory, and fluent speech. Cranial nerves II – XII were intact: pupils equal and reactive; visual fields full; extraocular movements full without nystagmus; facial strength symmetric; palate elevating midline; tongue midline. Motor examination showed 5-/5 strength diffusely with normal bulk and tone, and no pronator drift. Sensation to light touch was intact throughout. Reflexes were 2+ and symmetric, and coordination testing was normal. No focal neurological deficits were present. Kernig and Brudzinski signs were absent. CT head without contrast and MRI head with and without contrast showed no acute intracranial abnormality, with no diffusion restriction or meningeal enhancement. Lumbar puncture was performed in the left lateral decubitus position with the patient’s legs flexed and without sedation or Valsalva maneuvers. The CSF opening pressure was 42 cm H₂O. Approximately 15 – 20 mL of CSF was removed; the patient experienced immediate relief of her headache, with gradual improvement thereafter. No closing pressure was documented. Bedside fundoscopy demonstrated no papilledema. Given the markedly elevated opening pressure, cerebral venous sinus thrombosis was considered; however, clinical suspicion remained low in the absence of focal deficits, prothrombotic risk factors, or suggestive imaging findings, and MR venography was deferred. After the lumbar puncture, the patient was started empirically on dexamethasone (8 mg IV q6hr), ceftriaxone (2 G IV q12hr), vancomycin (1 G IV q12hr), and acyclovir (10 mg/kg/dose IV q8hr, based on the patient’s actual body weight: 53 kg) for presumed meningitis. Baseline renal function was normal, with a serum creatinine of 0.7 mg/dL and no evidence of chronic kidney disease. The patient received adequate IV hydration throughout therapy to reduce the risk of acyclovir-associated nephrotoxicity. Renal function was monitored daily; creatinine levels remained stable, and no dose adjustments were required during treatment. Dexamethasone was initiated due to concern for bacterial meningitis (particularly pneumococcal).

CSF studies Table 1 demonstrated an elevated WBC count with lymphocytic predominance. A diagnosis of aseptic lymphocytic meningitis was made. The initial CSF multiplex panel was negative Table 2. Targeted CSF HSV PCR Table 3 confirmed HSV-2-associated aseptic meningitis (Mollaret’s Meningitis).

Blood and CSF cultures had been obtained before the initiation of antibiotics, and CSF cultures showed no growth at 72 hours (with blood cultures later finalizing as no growth at 5 days). During this period, the patient demonstrated clinical improvement, and CSF analysis revealed lymphocytic-predominant pleocytosis consistent with viral meningitis; ceftriaxone, vancomycin, and dexamethasone were discontinued. Once targeted HSV CSF PCR confirmed HSV‑2, Acyclovir was also discontinued, and the patient was managed with supportive care in accordance with current guidelines.

She was discharged with neurology and ophthalmology follow-up for interval reassessment of headaches and visual symptoms, including repeat funduscopic evaluation if symptoms recurred or persisted. Return precautions were emphasized for worsening headache, vomiting, visual obscurations, or diplopia. She was also counselled on the natural course of HSV-2 meningitis/Mollaret’s syndrome, including the possibility of recurrent episodes of aseptic lymphocytic meningitis that typically resolve spontaneously over several days. Timeline of events and findings shown in Table 4.

Discussion

The clinical profile of our patient, severe headache with photophobia and fever, lymphocytic CSF pleocytosis, and HSV-2 PCR positivity, supports the diagnosis of Mollaret’s meningitis. Episodes are typically abrupt and self-limited over several days, followed by symptom-free intervals. Studies suggested that viral infections may potentially cause Mollaret’s meningitis. In particular, HSV-2 has been implicated in causing recurrent meningitis episodes in some individuals [¹,²,³].

Diagnostic criteria and epidemiology continue to evolve. Bruyn et al. published criteria for the diagnosis of Mollaret meningitis, defined as recurring episodes presenting with severe headache, meningismus, and fever in the absence of a detectable etiological agent [⁸]. Recent cohorts focused on HSV 2 – associated disease have applied less stringent thresholds (e.g., $\geq$2 episodes) and quantified rarity: a nationwide Danish cohort estimated an annual incidence of ~1.2 per 1,000,000 adults, underscoring how easily this condition is underrecognized [⁹,⁴].

Pathophysiologically, the prevailing model posits that HSV-2 latency and reactivation are linked to host susceptibility. The viral component is supported by repeated PCR confirmation during symptomatic windows and the consistency of the clinical phenotype [¹,²,³]. Mechanistically, host factors now feature prominently: whole exome sequencing and functional immunologic studies in recurrent HSV-2 meningitis (Mollaret meningitis) demonstrate possible defects in interferon signaling and autophagy/ubiquitin pathways, which may help explain why inflammatory changes can persist beyond symptom resolution in some patients [⁷].

Differential diagnosis remains important whenever presentation or testing is atypical. Although HSV-2 is most frequently implicated, HSV-1, VZV, EBV, HHV-6, and even enteroviruses have been documented in recurrent aseptic meningitis with Mollaret features, and non-infectious mimics, such as epidermoid cyst leakage, can also produce recurrent lymphocytic CSF with “Mollaret cells” [⁵,¹⁰,¹]. Recognizing these alternatives prevents premature anchoring and encourages repeat CSF analysis and appropriately timed virologic testing during symptomatic windows, particularly when initial multiplex panels are negative, as occurred in our patient before targeted HSV PCR established the diagnosis [¹⁰,¹,²,³]. In our case, the differential was addressed by (i) normal non contrast head CT and brain MRI without mass lesion or extra axial process, (ii) a CSF profile demonstrating lymphocytic pleocytosis with elevated protein and normal to slightly high glucose, (iii) negative Gram stain, bacterial cultures, and a comprehensive CSF meningitis/encephalitis multiplex PCR panel for bacterial and non HSV viral pathogens, and (iv) a subsequently positive targeted CSF HSV 2 PCR obtained during the symptomatic window. Collectively, these findings render alternative viral etiologies (HSV-1, VZV, enterovirus, HHV-6), bacterial meningitis, and non-infectious mimics unlikely, while CSF HSV-2 PCR positivity provides a specific etiologic diagnosis consistent with Mollaret’s meningitis.

Management is primarily supportive during acute episodes (analgesia, hydration, antiemetics), with many clinicians administering acyclovir/valacyclovir to expedite symptom control, consistent with case-based practice and guideline-consistent care [¹,²,³]. The role of long-term suppressive antivirals remains controversial. A pivotal randomized, double blind trial of valacyclovir suppression after HSV-2 meningitis did not demonstrate a reduction in recurrences, suggesting that routine suppressive therapy should be individualized rather than reflexive [¹¹]. The heterogeneity in recurrence frequency, symptom burden, and patient comorbidities supports a tailored approach that emphasizes patient education on early re-presentation and the avoidance of unnecessary antibiotics once bacterial etiologies are excluded [¹¹,⁶,⁴,²].

Finally, neuroophthalmic manifestations (e.g., papilledema, cranial nerve palsies) have been described in Mollaret’s meningitis and may reflect intracranial pressure dynamics and transient inflammatory effects on the visual pathways [¹²], which are relevant to the photophobia and severe headache prominent in our case. These features, together with our patient’s raised opening pressure, underscore that Mollaret meningitis, while often self-limited, can exert meaningful physiological impact during and beyond the symptomatic window.

Conclusion

In summary, this case demonstrates an episode of HSV-2-associated aseptic meningitis confirmed by CSF PCR in a patient with a history of prior meningitis and a markedly elevated opening pressure. Two key clinical takeaways emerge from this presentation: (1) HSV 2 should be considered in patients with recurrent aseptic lymphocytic meningitis, particularly when CSF demonstrates a lymphocytic profile with a compatible clinical history; and (2) significant intracranial hypertension can accompany HSV-2 meningitis and warrants a structured evaluation and follow-up plan. The patient was discharged with neurology and ophthalmology follow-up to monitor for recurrent symptoms, reassess for papilledema, and provide early evaluation should future episodes occur.