ORIGINAL ARTICLES

Cytology of Mollaret Meningitis Hilary Evans, M.D., F.I.A.C

The diagnosis of Mollaret meningitis was established by cytologic examination of the cerebrospinal fluid (CSF) in a patient with recurrent aseptic meningitis. The characteristic features of the “Mollaret cell,” an activated monocyte, are presented; theories of etiology are reviewed. Diagn Cytopathol 1993;9:373-376. CQ 1993 Wiley-Li\s, Inc

Key Words: Recurrent aseptic meningitis; Cerebrospinal fluid monocytosis; Mollaret cell

Mollaret meningitis is a recurrent aseptic meningitis with characteristic clinical and spinal fluid cytologic findings. Considered rare, it receives little space in textbooks. Less than 50 cases have been reported. Within the past 4 years, two cases have been diagnosed at our 287-bed community hospital. This raises the possibility that the disease may be more common than is appreciated and may often go un- diagnosed.

The spinal fluid cytologic findings are characteristic and essential to the diagnosis. Therefore, the cytology of Mol- laret meningitis will be presented.

Clinical Findings An attack of Mollaret meningitis is characterized by the sudden onset of fever, nausea and vomiting, headache, neck pain and stiffness, muscle aches, and positive Kernig and Brudzinski signs. Within a few hours, the neurologic signs reach their maximum and often include coma, grand ma1 seizures, syncope, delirium, hallucinations, anisoco- ria, absence of abdominal reflexes, visual disturbances, diplopia, speech impairment, dysequilibrium, facial pare- sis, and unilateral or bilateral Babinski reflexes. No other organ system is involved.

After 1 to 7 days of illness, all signs and symptoms disappear as rapidly as they developed, and the patient is entirely well until the next episode. The length of the

Received April 20, 1992. Accepted September 17, 1992. From the Department of Pathology, Lee Hospital, Johnstown, PA. Address reprint requests to Hilary Evans, M.D., F.I.A.C., Depart-

ment of Pathology, Lee Hospital, 320 Main Street, Johnstown, PA 15901-1694.

interval between attacks varies from days to years. The symptom-free intervals are longer at the outset and to- ward the end of the illness. The patient may experience dozens of attacks over a period of years. The illness finally ceases as suddenly as it began.

Spinal Fluid Findings Bacterial culture of the cerebrospinal fluid (CSF) is nega- tive. A pleocytosis of up to several thousand cells per cubic millimeter is seen within the first 24 hours. These are neutrophils and large mononuclear cells-“Mollaret cells.” After the 1st day of the attack, the neutrophils are replaced by lymphocytes as the predominant cell. Within a few days, the lymphocytes also disappear. The mononu- clear cells are most prominent during the neutrophilic phase of the pleocytosis, when they may comprise up to 66% of the cells. During the acute stage, the spinal fluid is under increased pressure. CSF protein is elevated, and the gamma globulin fraction is high. Glucose is low-nor- mal, and occasionally is decreased.

Case Report The first case seen at our hospital has been previously reported.

The patient under consideration here is a 69-year-old woman with two admissions to other hospitals for menin- gitis within the previous 5 years. She experienced the sud- den onset of fever, confusion, and stiff neck. On examina- tion, the only positive findings were disorientation in time and place, temperature 101.4”F, and stiffness of the neck to forward flexion. CSF exam on the day of admission showed 83 WBC/mm3 with 85 polys and 15 lymphs. Glucose was 62 mg/dL (40-75). Cytologic examination was not obtained on this fluid. Gram stain and bacterial culture were negative. Electroencephalogram was normal. CT scan and MRI showed no lesions. Because of the past history and these findings, the diagnosis of Mollaret men- ingitis was considered, and a second spinal tap was per- formed, 48 hours after admission. It showed WBC 24/ mm with 1 poly and 99 lymphs. Glucose was 67 mg/dL, protein 84 mg/dL (15-45). Bacterial culture was negative,

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as were blood cultures. Cytologic examination was ob- tained (Figs. 1-4). The diagnosis of Mollaret meningitis was made. By the 3rd hospital day the patient was ori- ented and afebrile. She was discharged on the 7th day, asymptomatic.

Cytologic Findings Cytocentrifuge preparations were made and stained by the modified Papanicolaou method. The smears consisted of lymphocytes and mononuclear cells, with an occasional neutrophil (Fig. 1). The mononuclear cells formed a few clusters (Fig. 2) , but most of them occurred singly (Figs. 3, 4).

3 p m in diame- ter and were irregularly round. The cytoplasm was faint

The mononuclear cells measured 18

green and finely vacuolated. The nuclei were eccentrically located and irregularly shaped, often forming a “hof,” as is common in monocytes. Many of the nuclei had large, irregular chromocenters with associated clearing of the parachromatin. There were also irregular deposits of chro- matin on the chromatinic rim. Micronucleoli were noted in some of the cells. Neither cytoplasmic nor nuclear in- clusions were present.

The Mollaret Cell Mollaret in 1944 considered the characteristic cell to be endothelial, although he questioned this 33 years later. Electron microscopy 5s7 and immunocytochemistry have confirmed that the cell is a monocyte.

The tendency of these cells to group together (Fig. 2) was noted by Mollaret, who speculated that they had been desquamated from the choroid plexus.

Fig. 1. Lymphocytes, mononuclear cells, and one neutrophil. The de- generating cells at the bottom are probably mononuclear cells. (Papani- colaou, x 1,000.)

Fig. 2. Tendency of monocytoid cells to group together in clusters. (Papanicolaou, X 400.)

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CYTOLOGY OF MOLLARET MENINGITIS

Fig. 3. Monocytoid cells. The cells are irregularly round and approxi- mately 20 p m in diameter. The cytoplasm is faint, finely vacuolated, and has an indistinct margin. The nuclei are eccentrically located. The chro- mocenters are large and irregular; one is located at the chromatinic rim; and the parachromatin is irregularly cleared. The upper cell has a “hof.” (Papanicolaou, x 1,000.)

The Mollaret cell has the characteristics of an activated monocyte. Blood monocytes, together with mesothelial cells of the pia and arachnoid, make up the leptomingeal reticuloendothelial system. Irritation of the leptomenin- ges, such as occurs during the granulocytic phase of this condition, would cause these monocytic cells to exfoliate.

The fragility and light staining of Mollaret cells makes them difficult to recognize in a counting chamber. Cyto- logic examination is essential to identify these cells.

Differential Diagnosis Large monocytes are seen in other types of meningitis, but their presence in large numbers-up to 66%-has not been described in any other disease. Hermans, in his exten- sive literature review, listed more than 25 conditions in which recurrent meningitis is found. In all conditions

Fig. 4. Spectrum of monocytoid cells. (Papanicolaou, x 1,000.)

other than Mollaret meningitis, there is involvement of other organ systems.

Etiology No etiology for Mollaret meningitis has been established. In one case, herpes simplex type I was isolated lo; and one other case was associated with Epstein-Barr mononucleo- sis. Despite these findings, no consistent viral etiology has been found in extensive studies.

One investigation of peripheral blood mononuclear cells during an acute attack of Mollaret meningitis demon- strated increased circulating natural killer cells and noted the morphologic similarity of these peripheral blood cells to the Mollaret cells in the CSF. The authors speculated that the natural killer cells in the peripheral blood had proliferated in response to a virus and that they then migrated to the central nervous system, where they ap- peared in the CSF as Mollaret cells. l 2 This hypothesis has not been further investigated.

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The occurrence of Mollaret meningitis in three patients with recurrent hereditary polyserositis (RHP) has been noted. The two conditions have many similar features, and the authors propose that they are different manifestations of a single disease. RHP is restricted to certain ethnic groups. l3 The hypothesis that Mollaret meningitis is the same disease as manifested in different ethnic groups is interesting but would be difficult to test.

Recently, two groups of investigators have noted the similarity of Mollaret meningitis to ruptured central ner- vous system epidermoid cyst and have proposed that these are the same disease. 14,15 CT scans are characteristically negative during an attack, presumably because of empty- ing of the cyst. The diagnosis is made by performing a CT scan between attacks. l4 It has been further speculated that the ‘Sfunt6mes celluluires” (cell ghosts) described by Mol- laret l 5 were not the mononuclear cells now known as “Mollaret cells,” but were superficial squamous epithelial cells from a ruptured epidermoid cyst. l 6 This hypothesis should be tested by obtaining appropriate imaging studies on Mollaret meningitis patients between attacks.

Conclusions Mollaret meningitis should be suspected in any patient with recurrent aseptic meningitis. The diagnosis is estab- lished by cytologic examination of CSF, obtained early in the course of the attack, preferably within the first 24 hours.

Acknowledgment Dr. Brian P. Ahlstrom, consulting neurologist, made the clinical diagnosis of Mollaret meningitis. Mr. Ronald Blaney prepared the photomicrographs.

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