Neuro-ophthalmic Manifestations of Mollaret Meningitis

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Article initiated by:

Andrew Go Lee, MD, Nagham Al-Zubidi, MD, Noor Laylani, M.D., Pamela Davila-Siliezar, MD, Patrick J. Hunt, Jeel Mehta

All contributors:

Nagham Al-Zubidi, MD, Noor Laylani, M.D.

Assigned editor:

Osama Al Deyabat, MBBS

Review:

Assigned status Update Pending

 by Osama Al Deyabat, MBBS on November 7, 2022.

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Contributing Editors:	add

Disease Entity

Epidemiology

Mollaret meningitis (MM), also known as recurrent benign lymphocytic meningitis (RBLM), is a rare, recurrent form of aseptic meningitis. The episodes typically last 2-7 days and then resolve spontaneously. MM is more common in women and has an average onset age of 35 years. The number of recurrences usually varies between 3 and 8. The interval between episodes is also variable from weeks to years, and there is no discernible pattern. The typical symptoms of MM include fever, headache, nausea, vomiting, nuchal rigidity, and generalized myalgia. In rare cases, more severe symptoms, including seizures, altered consciousness, and upper motor neuron damage have been reported. Importantly, neurological symptoms of MM resolve completely between episodes. Neuro-ophthalmological manifestations of MM are uncommon but included anisocoria, optic neuritis, papilledema, cranial nerve 6 (CN6) palsy, uveitis, blepharoconjunctivitis, and disc edema with normal opening pressure.

Although many patients with MM report prior herpes simplex virus Type 2 (HSV-2) infections, most patients have no preceding infection. In many of these patients, HSV-2 positivity or the presence of HSV-2 antibodies on cerebrospinal fluid (CSF) analysis suggests a prior asymptomatic infection. Recurrent aseptic meningitis however has been associated with a number of immune-mediated illnesses, including systemic lupus erythematosus, familial Mediterranean fever, Behçet disease and sarcoidosis, and rarely a chemical meningitis from an intracranial epidermoid cyst that may mimic MM. An immune mechanism has been postulated for MM and cases have been described in Good syndrome, IgG subclass 2 immunodeficiency, and suspected common variable immunodeficiency. Patients should be evaluated carefully for an epidermoid cyst-mediated meningitis which can present with up to 30 or more episodes compared to the 3 – 8 episodes typically seen in patients with MM. In the case of epidermoid cyst-associated MM, meningeal irritation is thought to be an immunological response to intermittent leakage of squamous material from the cyst into the CSF. MM has also been described in pregnant patients and alterations to immune system function during pregnancy is believed to be the cause.

Pathogenesis

Although Mollaret initially suspected a viral etiology, the pathogenesis of MM remains ill defined. Reports from polymerase chain reaction (PCR) analysis of the CSF demonstrate that MM may be associated with latent HSV-2 infections. Alternatively, episodic, aseptic meningitis, consistent with MM, has also been reported during HSV-1, varicella zoster virus, echovirus, coxsackie virus, and Epstein-Barr virus infections. However, the majority of presumed viral cases of MM have HSV-2 positivity in the CSF. Latent HSV-2 residing within cranial ganglia and dorsal root ganglia may spread to the meninges via CSF, resulting in the observed lymphocytic inflammatory response.

Diagnosis

Symptoms and signs

The symptoms and signs of MM vary from patient to patient, but may include the following symptoms listed in Table 1. The reported neuro-ophthalmic findings are summarized in Table 2.

Table 1: Typical symptoms and signs in MM

• Meningismus
• Fever
• Severe headache
• Nausea & vomiting
• Generalized myalgia
• Seizures
• Altered mental state
• Upper motor neuron damage
• Painful clustered vesicular rash on an erythematous base consistent with HSV-2 infection

Table 2. Reported neuro-ophthalmologic symptoms of MM

• Anisocoria
• Optic neuritis
• Papilledema
• CN6 palsy
• Diplopia
• Uveitis
• Blepharoconjunctivitis
• Optic disc edema with normal opening pressure

Cytological analysis of the CSF in MM demonstrates lymphocytic predominant pleocytosis. During the first 24 hours of symptom onset, large atypical monocytes with footprint nuclei, now commonly known as Mollaret cells, can also be observed. These cells have increased fragility, and their degenerated cellular forms, described as “fantomes cellulaires” (cell ghosts) by Mollaret, are often seen on CSF cytology analysis. Though not pathognomonic, these cells are highly characteristic of MM.

In the majority of MM, PCR analysis of the CSF during an episode of MM will reveal HSV-2 positivity in the absence of growth on CSF viral cultures. Transient increases in CSF protein levels coincide with episodes of MM, consistent with a viral- or immune-mediated etiology. Interestingly, however, decreased CSF glucose concentrations are not uncommon during episodes, which is inconsistent with the classic teaching on the CSF correlates of viral- or immune-mediated meningitis, and might suggest an alternative or additional process. Meningitic episodes that present as a result of epidermoid cyst leakage can be difficult to definitively diagnose. Suspicion for an epidermoid cyst may be high, especially in patients who present with greater than 8 episodes of transient aseptic meningitis. However, because epidermoid cysts often collapse following leakage of fluid, these cysts are not easily visualized during episodes of meningitis, and must be visualized during asymptomatic periods. Polarizing microscopy of the CSF can detect evidence of cystic leakage in the intradural space, and can serve as an adjunct technique in cases that are difficult to diagnose.

Diagnostic Criteria

Inclusion Criteria

• Three or greater recurrent episodes of headaches, meningismus, and fever
• Lymphocytic pleocytosis, with neutrophils and monocytes on CSF cytology analysis
• Complete resolution of symptoms between episodes
• Spontaneous resolution of symptomatic episodes

Exclusion Criteria

• Identifiable alternative etiology

Differential Diagnosis

The differential diagnosis of MM is summarized in Table 3.

Table 3: Differential diagnosis of MM

• Enterovirus aseptic meningitis
  • Coxsackievirus
  • Echovirus
• Human Immunodeficiency virus (HIV) meningitis
• Lymphocytic choriomeningitis virus
• Mumps meningitis
• Spirochete meningitis
  • Treponema pallidum (syphilis)
  • Borrelia burgdorferi (Lyme disease)
• Fungal meningitis
  • Cryptococcus
  • Candida (especially after cranial instrumentation)
  • Coccidioides
• Tuberculous meningitis
• Bacterial meningitis
  • Partial resolution of prior infection
  • In conjunction with immunodeficiency
  • Acquired anatomic defects
• Parasitic meningitis
  • Angelostrongyloides
  • Echinococcosis
  • Strongyloides stercoralis
  • Toxoplasma gondii
• Malignant neoplasms
  • Leptomeningeal metastatic spread
• Benign tumors
  • Craniopharyngiomas
• Drug-induced aseptic meningitis (DIAM)
• Syndrome with brief headaches and neurological impairments with CSF lymphocytosis (xiii) (HaNDL)

Management

Medical Therapy

While MM can be treated with supportive measures alone, it is often empirically treated with 7-14 days of IV acyclovir at a dose of 10 mg/kg every 8 hours. This is, in part, due to the similar presentation and CSF findings of MM with HSV-1 encephalitis, which is life-threatening and necessitates antiviral therapy. Given that MM is a recurrent disease, many studies have been performed to elucidate the optimal therapy to prevent recurrent episodes. However, no consensus on prophylactic treatment has been reached due to conflicting findings. Some studies have shown that valacyclovir provides long-term relief from recurrent episodes of MM, while others have shown no significant impact of valacyclovir prophylaxis on MM recurrence. In fact, one double-blind randomized control trial that compared valacyclovir 500 mg twice daily to placebo for one year and followed patients for the following year showed a significantly higher risk of MM recurrence in patients who had received valacyclovir. Colchicine has also had mixed results, preventing MM recurrence in some studies, but generally failing as effective prophylaxis. Therefore, further efforts are required to establish the appropriate secondary prevention therapy for MM.

Treatment for ocular manifestations

Papilledema is the most frequently encountered ophthalmic finding in patients with MM, and it should be managed once vision becomes affected. Medical management includes administration of acetazolamide up to maximally tolerated doses. Surgical management options include optic nerve sheath fenestration or CSF diversion procedures (e.g., ventriculoperitoneal shunt) for patients who fail maximum medical therapy and have persistent papilledema related visual loss.

Prognosis

MM is a recurrent but benign disease with an excellent prognosis in general. Symptoms during acute flares generally resolve spontaneously within days to several weeks. While patients can present acutely with neurological deficits, patients do not suffer from prolonged symptoms or long-term residual complications. Recurrent episodes are common but difficult to predict given the large variability in symptom-free intervals, which can range from a few days to years. The frequency of recurrences tends to decrease over time. Overall, most cases of MM have a favorable prognosis with no long-term neurologic sequelae.