Mollaret’s Meningitis

Mollaret’s Meningitis is a rare form of recurrent meningitis originally described by Mollaret in 1944. In 1962, Bryun proposed the clinical diagnostic criteria of:

• Recurrent episodes of severe headache, meningismus, and fever
• Cerebrospinal fluid (CSF) pleocytosis with large "endothelial" cells, neutrophils, and lymphocytes
• Attacks separated by symptom-free periods of weeks to months
• Spontaneous remission of symptoms and signs
• No causative etiologic agent detected.

In 1979, Goldi observed that Mollaret’s meningitis could occur without fever, have symptom-free periods from days to years, have increased CSF gamma globulin, and have transient neurologic signs and symptoms.

Clinical Presentation

Mollaret’s meningitis is characterized by repeated episodes of fever (up to 104oF), meningismus, and severe headache separated by symptom-free intervals. Individual attacks are sudden, with signs and symptoms reaching maximum intensity within a few hours. Headache, neck pain, generalized muscle aches, and neck stiffness usually persist from one to three days, but may be present for up to three weeks. Following a number of recurrences, which can span a period of years, the disease suddenly disappears. The long-term health of the patient seems not to be adversely affected. Transient neurologic abnormalities (seizures, diplopia, pathologic reflexes, cranial nerve paresis, hallucinations, and coma) occur in as many as 50% of cases. However, persistence of neurologic defects should call the diagnosis into question. CSF obtained early in the course of the illness usually demonstrates large, friable "endothelial" cells termed Mollaret’s cells. Mollaret’s cells can be demonstrated by the Papanicolaou stain, and are now considered to be large activated cells of monocyte/macrophage lineage. Mollaret’s cells are considered by many to be the hallmark of Mollaret’s meningitis, and early on may comprise 60% to 70% of the CSF cells. These cells are usually present for only the first 24 hours and can be missed easily. Furthermore, "Mollaret’s cells" are not pathognomonic for Mollaret’s meningitis. After the first 24 hours, the CSF shows a lymphocytic predominance with cell counts usually less than 3,000/mm3 [one case had 9,300 cells/mm3]. Hypoglycorrhachia, low CSF glucose concentration, is reported in one-third of patients. CSF protein, especially the gamma globulin fraction, is usually mildly elevated.

Etiology

Recent data suggest that Herpes simplex Type II and, less frequently, Herpes simplex Type I may be etiologic in some if not most cases of Mollaret’s meningitis. Picard et al. have reported three well documented patients with Mollaret’s meningitis, each of whom had Herpes simplex Type II DNA demonstrated in their CSF by the polymerase chain reaction (PCR)*. In a more recent study, Tedder et al. (Ann Int Med. 212:334-338, 1994) reported on thirteen patients with benign recurrent lymphocytic meningitis. Eleven of the thirteen patients had H. simplex Type II DNA demonstrated in their CSF by PCR. The remaining two patients had anti-H. simplex antibody demonstrated in their CSF. Although all thirteen of these patients fit most of the clinical diagnostic criteria for Mollaret’s meningitis, none had Mollaret’s cells demonstrated in their CSF. Furthermore, none of these thirteen patients showed the expected transition from a mainly neutrophilic pleocytosis early in the course to a mainly lymphocytic pleocytosis as the disease progressed. Thus, these patients may have presented with Mollaret’s meningitis without Mollaret’s cells being demonstrated, or they may represent a Mollaret’s-like syndrome caused by H. simplex Type II. Other etiologic agents that have been considered over the years include trauma and viral infections other than H. simplex. The differential diagnosis includes several diseases of unknown etiology (Behcet’s syndrome, sarcoidosis, and uveoencephalitis [Vogt-Koyanagi and Harada syndromes]) as well as neurenteric cyst of the foramen magnum and ruptured pineal cyst.

Therapy

Mollaret’s meningitis is a syndrome rather than a disease. As such, the syndrome of Mollaret’s meningitis appears to have multiple etiologies. Presently, H. simplex Type II, and to a lesser extent Type I, appear to be etiologic in most cases. Because of the rarity of this syndrome, there are no large clinical trials comparing one therapy against another. However, acyclovir (intravenous or oral) or valacyclovir (oral only) are worthy of consideration for both therapy and prophylaxis. Other therapies tried include steroids (no benefit) and colchicine 0.5 mg BID (apparent prophylactic benefit in some cases).

Points to Remember

Suggested Reading

*Picard FJ, Dekaban, GA, Silva J, and Rice GPA: Mollaret’s meningitis associated with Herpes Simplex type 2 Infection. Neurology 43:1722-1727. 1993.