Mollaret meningitis (MM), also called recurrent benign lymphocytic meningitis (RBLM), is a rare recurrent form of aseptic meningitis. It was first reported in 1944 by French neurologist Pierre Mollaret 1, 2).
The prevalence is estimated to be approximately 2/100,000 2). It is more common in women (about 70%), and the average age of onset is 35–40 years 2). Each episode typically lasts 2–7 days and resolves spontaneously. The number of recurrences is usually 3–8, and the interval between episodes varies widely from weeks to years. The frequency of recurrence tends to decrease over time.
Neuro-ophthalmic symptoms include papilledema, anisocoria, optic neuritis, abducens nerve palsy, diplopia, uveitis, and blepharoconjunctivitis. These ocular symptoms also disappear between episodes.
The number of recurrences is usually 3–8, and the interval between episodes varies widely from weeks to years among individuals. The frequency of recurrence tends to decrease over time, but when caused by intracranial epidermoid tumor, there may be 30 or more episodes.
Optic disc / Optic nerve
Papilledema: The most common ophthalmologic finding. Reflects increased intracranial pressure.
Optic neuritis: Due to spread of inflammation to the optic nerve.
Optic disc edema with normal opening pressure: Cases without increased intracranial pressure have also been reported.
Eye Movements and Others
Sixth cranial nerve (abducens nerve) palsy (CN6 palsy): Motor neuron damage to the lateral rectus muscle causes abduction deficit and paralytic esotropia. Bilateral mild abducens nerve palsy can occur with elevated intracranial pressure.
Anisocoria: Due to inflammatory spread to the autonomic nervous system.
Uveitis: Spread of intraocular inflammation.
Blepharoconjunctivitis: Involvement of the ocular surface by HSV-2.
The causes of Mollaret meningitis are diverse. The main classifications are shown below.
| Classification | Cause |
|---|---|
| Viral | HSV-2 (most common), HSV-1, varicella-zoster virus, EBV, echovirus, coxsackievirus |
| Autoimmune/autoinflammatory | SLE, familial Mediterranean fever (FMF), Behçet’s disease, sarcoidosis |
| Structural and other | Intracranial epidermoid cyst, immunodeficiency (Good syndrome, IgG subclass 2 deficiency, CVID) |
HSV-2 is detected in the majority of cases by CSF PCR and is the most common cause 1, 2, 5). HSV-2 can remain latent in cranial and spinal dorsal root ganglia and reactivate to cause meningitis.
Strict definitions limit MM diagnosis to non-infectious (CSF PCR-negative) cases, but with the widespread use of PCR, there is a shift toward including HSV-2-positive cases 1, 2). In HIV patients, HSV-2 co-infection rates are high (30–70%), increasing the risk of MM 4).
Chemical meningitis due to intermittent leakage of squamous epithelial components from an intracranial epidermoid cyst is also an important cause, and epidermoid-associated cases can present with more than 30 episodes 1). Because the cyst collapses after leakage, it may be difficult to identify on imaging at the time of symptom onset, and imaging evaluation during asymptomatic periods is necessary 1).
Cases of MEFV gene P369S/R408Q mutations have been reported in association with Kikuchi disease (histiocytic necrotizing lymphadenitis) 3).
Non-infectious (CSF PCR-negative) cases also exist. Various causes have been reported, including autoimmune diseases (SLE, Behçet’s disease, FMF), intracranial epidermoid tumors, drugs (NSAID-induced hypersensitivity reactions), and immunodeficiency states 1).
Mollaret cells are not a pathological definitive diagnosis but strongly support the diagnosis. Because they are fragile and easily lysed, early lumbar puncture after onset is important 1). Similar cells have also been reported in sarcoidosis, Behçet’s disease, varicella-zoster virus, and WNV, so specificity is limited 1).
The Bruyn diagnostic criteria (1962) and the Galdi modified criteria are shown below 1).
| Item | Bruyn Criteria (1962) | Galdi Modified Criteria |
|---|---|---|
| Fever | Required | Not required |
| Recurrence of meningeal irritation signs | Required | Required |
| Increased CSF cell count | Required | Required |
| Asymptomatic period | Several weeks to several months | Extended to several days to several years |
| Sequelae | None | None |
| Neurological abnormalities | Not described | Transient in about half |
| Causative microorganism | Not identified | Being revised with spread of PCR |
In HIV patients with CD4 <350, it is necessary to preferentially rule out opportunistic infections such as cryptococcosis 4).
CSF PCR is the gold standard, and detection of HSV-2 DNA confirms the diagnosis 5). Detection of Mollaret cells in lumbar puncture within 24 hours of onset also strongly supports the diagnosis. CSF PCR should always be performed in recurrent aseptic meningitis.
Although it may resolve spontaneously with supportive care alone, empirical antiviral therapy is widely used 1).
Note that there are case reports of a single dose of dexamethasone being used before diagnosis for severe meningitis symptoms5). NSAIDs have also been reported to improve acute-phase symptoms3).
There is no established preventive method. Prophylactic administration of valacyclovir has been considered, but in the RCT by Aurelius et al. (2012) (valacyclovir 500 mg twice daily vs placebo, 1-year administration + 1-year follow-up), the risk of MM recurrence was significantly higher in the valacyclovir group, and no preventive effect was demonstrated2).
Effective cases of recurrence suppression with colchicine have also been reported, but it is not a generally established preventive method (see “Latest Research and Future Prospects” section).
Papilledema
Acetazolamide: First-line medical management. Administer up to the maximum tolerated dose.
Optic nerve sheath fenestration: Surgical option when medical management is difficult.
CSF shunting (ventriculoperitoneal shunt, etc.): Considered when intracranial hypertension persists.
Abducens Nerve Palsy
Response to acute treatment: Abducens nerve palsy often resolves between episodes.
Observation: Bilateral mild abducens nerve palsy due to increased intracranial pressure is expected to improve with treatment of the underlying disease.
Prism glasses: Considered as symptomatic treatment for persistent diplopia.
Prophylactic antiviral therapy (valacyclovir) has been considered, but its efficacy was not proven in the RCT by Aurelius et al. (2012)2). Colchicine has also been reported effective in some cases, but it is not established. The frequency of recurrence tends to decrease over time.
The pathophysiology of Mollaret meningitis is not yet established, but several hypotheses have been proposed.
Latent HSV-2 infection and reactivation: This is considered the main mechanism. HSV-2 remains latent in cranial and dorsal root ganglia, and upon reactivation, it reaches the meninges via the CSF, triggering a lymphocytic inflammatory response.
Toll-like receptor 3 (TLR3) deficiency hypothesis: Willmann et al. proposed that deficiency of TLR3, which is involved in the innate immune response to viruses, may predispose individuals to HSV-2-associated MM 1).
Cytokine hypothesis: Elevated levels of IL-6 and TNF-α in the CSF have been reported, suggesting excessive cytokine release due to latent viral infection 1).
NLRP3 inflammasome pathway: Colchicine inhibits NLRP3, reducing secretion of IL-1β, IL-6, and IL-18. This is considered a possible mechanism explaining the efficacy of colchicine in MM associated with Kikuchi disease 3).
MEFV gene mutations: The P369S/R408Q mutations are associated with atypical clinical features of familial Mediterranean fever (FMF) and have been suggested to be linked to Kikuchi disease and MM 3). Case reports of positive CSF oligoclonal bands support an immunological mechanism 3).
Intracranial epidermoid hypothesis: An immune reaction to squamous epithelial components intermittently leaking from the cyst triggers episodes of meningitis. After an episode, the cyst may be collapsed and difficult to detect on imaging, so CT or MRI evaluation during asymptomatic periods is necessary1).
EBV-related hypothesis: Reactivation of latent CNS infection after primary EBV infection has been proposed as a possible mechanism1).
Inflammatory lesions in the brainstem (midbrain, pons, medulla oblongata) can cause various eye movement disorders. Dorsal midbrain syndrome (Parinaud syndrome) includes upward gaze palsy, convergence palsy, light-near dissociation, convergence-retraction nystagmus, and eyelid retraction (Collier sign). Midbrain aqueduct obstruction may be complicated by papilledema.
Handa et al. (2024) attempted colchicine in a 41-year-old Japanese woman with MEFV gene P369S/R408Q mutation (21-year history of recurrent MM complicated by Kikuchi disease) 3). Starting at 0.5 mg/day, recurrence was observed at 1.0 mg/day, so the dose was increased to 1.5 mg/day, resulting in suppression of recurrence for 1.5 years. Prednisolone 15–20 mg/day was insufficiently effective. The mechanism is thought to involve colchicine’s inhibition of the NLRP3 inflammasome (suppression of IL-1β, IL-6, and IL-18 production).
This case has a specific genetic background, and its application to general MM has not been established.
In the RCT by Aurelius et al. (2012), valacyclovir 500 mg twice daily vs. placebo was administered for 1 year with 1-year follow-up, but the risk of MM recurrence was significantly higher in the valacyclovir group, and no preventive effect was demonstrated 2). Establishing long-term prophylactic therapy for HSV-2-associated MM remains a future challenge.
The HSV-2 co-infection rate in HIV-infected individuals is reported to be approximately three times that of the general population, raising concerns about an increase in MM cases 4). When the CD4 lymphocyte count exceeds 500, it is important to consider non-opportunistic infections and provide appropriate HSV-2 treatment 4).
Haider et al. (2025) reported a case of misdiagnosis persisting for several years, highlighting the decline in quality of life due to anxiety and depression from recurrent episodes and the importance of psychiatric liaison 5). Early diagnosis through widespread use of CSF PCR and avoidance of unnecessary broad-spectrum antibiotics are emphasized as key issues.
