Mollaret's Meningitis: CSF Cytology to the Rescue
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.299162
Source of Support: None, Conflict of Interest: None
Keywords: CSF cytology, herpes simplex virus, Mollaret's cells, Mollaret's meningitis
Mollaret's meningitis refers to the classical description by Pierre Mollaret of recurrent episodes of fever and meningism lasting 2–5 days, followed by spontaneous recovery. It remains a rare entity and most often is attributed to reactivation of latent herpes simplex virus (HSV)-2. Though considered self-limiting and innocuous, there are exceptional cases in which undesirable neurological sequelae have been reported. From a clinician's perspective, narrowing down the diagnosis may not be straightforward and would require judicious use of investigations.
Here, we report two cases of Mollaret's meningitis, in whom, cerebrospinal fluid (CSF) polymerase chain reaction (PCR) for HSV was negative. These reports also highlight an unusual pattern of presentation of this rare entity and the utility of CSF cytology in clinching the diagnosis.
A 50-year-old lady had repeated episodes of fever, agitated delirium followed by depressed sensorium and confused speech, which would gradually wear off over 3–6 days with mild episodic verbal and visual memory loss that would resolve over the subsequent weeks. Prior to the initial presentation at our center, she had three such episodes over the preceding 7 years and one was associated with secondarily generalized seizures. Her MRI, EEG, and CSF study done during two of her previous episodes were normal. She was initially admitted during her fourth episode during which she had extensive evaluation and her CSF study showed mild lymphocytic pleocytosis (total cells 6/cumm, all lymphocytes) and CSF PCR panel including HSV 1 and 2 PCR, EEG, MRI with contrast, workup for metabolic causes including urea cycle disorders and toxicology levels, all being normal. In the absence of a positive CSF HSV PCR, she was not treated with acyclovir. Exactly 1 year later, she presented with the worst attack yet during which she had fever, headache followed by coma and recurrent seizures and had to be ventilated. Evaluation during this admission showed mild diffuse leptomeningeal contrast enhancement, diffuse slowing in EEG consistent with encephalopathy, and normal metabolic parameters. Her CSF done 36 hours h after the onset of symptoms showed elevated protein (102.7 mg/dL), normal CSF glucose (162 mg/dL, RBS 228 mg/dL), total count 6 lymphocytes/cumm and her CSF PCR panel including HSV 1 and 2 was negative. Her CSF cytology was done immediately after the spinal tap revealed scattered large monocytoid cells with abundant cytoplasm and irregular lobulated nuclei suggestive of Mollaret's cells [Figure 1]. She was started on acyclovir and phenytoin and over the days made rapid recovery was extubated on day 3 and discharged with no neurological sequelae after 5 days. She was advised to complete 10 days of acyclovir and remains asymptomatic at 3 months follow-up.
A 9-year-old girl presented with 3 days history of fever, headache and vomiting with no other neurological findings except meningeal signs. She had a similar episode 3 years back and had been diagnosed as aseptic meningitis. Her MRI revealed mild diffuse meningeal enhancement along cerebral convexities and CSF study showed a total count of 114 cells/cumm, lymphocytic pleocytosis (92%) with elevated protein (74.3 mg/dL) and normal glucose (58 mg/dL, RBS 124 mg/dL). CSF cytology showed monocytoid cells with nuclei of uneven width, some with footprint appearance consistent with Mollaret cells. [Figure 2]. Her CSF PCR panel was negative but serology revealed elevated HSV 2 IgM. She was treated with acyclovir which was continued for 7 days. She had no recurrence and remains asymptomatic at 6 months.
These two cases highlight the varied presentation of Mollaret's meningitis and the utility of CSF cytology in reaching a diagnosis in the absence of PCR confirmation. While better described as idiopathic recurrent benign lymphocytic meningitis, the causative role of HSV 2 virus in clinically indistinguishable viral meningitis was shown by Yamamoto in 1991 and has since become synonymous.
Retrospective case series by Tedder and also by Vourinen have shown 85% to 79% positivity for CSF HSV DNA PCR, mainly HSV 2. Those patients in whom HSV DNA PCR was negative, no other causative agents were identified. Moreover, in some of the patients, in whom earlier attacks had revealed CSF HSV viral DNA, repeated testing during subsequent recurrences failed to reveal viral DNA. There was no difference in either clinical features or CSF picture between these two presentations. It may be inferred that while being specific, CSF PCR may not be highly sensitive for HSV-associated Mollaret meningitis. Various factors such as the timing of the test and the assay employed may act as confounding factors. Other viral agents such as cytomegalovirus (CMV), Epstein Barr virus (EBV) and enterovirus have been postulated to be causative but the association has not been conclusively proven. In both our cases, immunological testing for dengue, CMV, EBV viruses, and CSF PCR for enterovirus were negative.
The presence of Mollaret's cell in CSF is the hallmark feature of Mollaret meningitis. These cells are large mononuclear cells of monocyte/macrophage origin, with large convoluted nuclei with cytoplasmic pseudopods which can give the eye-catching appearance of “cloverleaf,” “bean,” or “footprint.” These cells are evanescent and are demonstrated usually in the first 24 h and can quickly degenerate to blurry phantom cells. In fact, in a retrospective case series by Mateen et al., where patients were selected based on clinical features and detection of HSV 2 PCR in CSF, Mollaret's cells were not detected in any of the 28 patients.
A second attack of acute meningitis in a patient without predisposing immunosuppression or recurrent source of infection such as CSF rhinorrhea should raise the suspicion for Mollaret's meningitis. While the lymphocytic CSF picture would raise broad possibilities, the acute presentation and rapid recovery in 1–3 days in most cases, seldom seen even in the setting of an appropriately initiated antibiotic therapy would be a pointer. In case 1, it was the previous presentation that made a strong case for Mollaret's meningitis. In such acute meningitis or encephalitic presentation, a pointed inquiry for a similar past history assumes importance, without which Mollaret's meningitis cannot be among the forefront of differentials. Since the Mollaret's cells in preserved CSF samples are evanescent, requesting CSF cytology in the fresh sample for every case of recurrent meningitis would be meaningful.
While the typical presentation has been acute onset self-limiting signs and symptoms of meningism, rare reports of memory impairment, paresthesia, vertigo, and poor concentration have been described. Case 1 is unique in that the patient had seizures with two of the recurrences. There was no alternate etiology for seizures and in authors' knowledge would be the first case of Mollaret's meningitis to be associated with a seizure. Though the patient had a favorable outcome and remains asymptomatic at 3 months, the latest presentation was far from innocuous and was life-threatening. Though a clear recommendation was lacking, both patients received a full course of intravenous acyclovir (during the second admission for case 1). A randomized control trial for valacyclovir to prevent recurrence after HSV meningitis has failed to show any benefit.
These two cases highlight idiopathic cases of recurrent lymphocytic meningitis befitting the eponym of Mollaret's meningitis as opposed to benign recurrent lymphocytic meningitis secondary to HSV. It reiterates the utility of CSF cytology in the diagnosis of such cases. An early lumbar puncture and cytology in fresh specimens should be part of the armamentarium in the evaluation of meningitis/meningoencephalitis syndrome. Besides mostly being a benign short-lasting self-limiting entity, Mollaret's meningitis has the rare propensity to have more serious, unexpected and life-threatening presentations. The association with HSV 2 reactivation may not be proven at all times and early CSF analysis would help in diagnosis.
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[Figure 1], [Figure 2]