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Marwan Shalabi, Richard J. Whitley, Recurrent Benign Lymphocytic Meningitis, Clinical Infectious Diseases, Volume 43, Issue 9, 1 November 2006, Pages 1194–1197, https://doi.org/10.1086/508281
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Abstract
Recurrent benign lymphocytic meningitis is a recurring, typically innocuous, painful form of aseptic meningitis. This syndrome is associated with transient neurological symptoms in one-half of afflicted patients. The causative agent is usually herpes simplex virus type 2, which can be confirmed by detection of viral DNA in the cerebrospinal fluid using polymerase chain reaction. Clinical disease resolves spontaneously; however, acyclovir, valacyclovir, and famciclovir have been administered to some patients for both episodic therapy and suppression of recurrences. This therapy is thought to be beneficial, although there is no controlled trial data to support efficacy and safety.
Recurrent benign lymphocytic meningitis (RBLM) was first described in 1944 by the French neurologist Pierre Mollaret [1]. Hence, the name “Mollaret meningitis” is frequently associated with the syndrome. This syndrome has also been called benign recurrent aseptic meningitis, benign recurrent meningitis, benign recurrent endothelial meningitis, benign recurrent endothelial-leukocytic meningitis and recurrent aseptic meningitis [2]. Here, we will use the designation “RBLM” as we summarize existing knowledge of this disease.
Clinical Presentation
RBLM is a rare illness that manifests as a benign, recurrent form of aseptic meningitis and is characterized by as few as 3 to at least 10 episodes of fever and meningism lasting 2–5 days, followed by spontaneous recovery [1, 3]. There is significant patient-to-patient variability regarding the time to recurrence; it may vary from weeks to months or even years. Over time, recurrences become less common, although data from prospective studies that support this assertion are limited. Indeed, some studies suggest that patients who have <3 episodes of meningitis should not receive a diagnosis of RBLM [4].
Patients with RBLM present with acute onset of headache that can be severe, as well as fever, photophobia, and meningism. The episodes are painful but self limited. Signs and symptoms reach maximum intensity within a few hours of onset. Each episode typically lasts 1–3 days, but 1 report recorded persistence of symptoms for 3 weeks with subsequent recurrences every few weeks [5]. Whether the prolonged duration of this illness in this instance was related to comorbid factors is unknown.
Approximately one-half of patients have transient neurological manifestations, including seizures, hallucinations, diplopia, cranial nerve palsies, or altered levels of consciousness. These symptoms are transient and, if they persist, a diagnosis of RBLM should be excluded.
Although RBLM is a rare illness, 3 series summarize the body of knowledge about the disease. Tedder et al. [4] described a group of 13 patients with RBLM; their demographic characteristics appear in table 1. Kupila et al. [6] described 14 patients; their demographic characteristics appear in table 2. The third report described the cytopathologic findings of CSF samples, but reviewed few clinical data regarding this patient population (table 3) [7]. From these reviews, several findings are obvious. First, among the 41 patients who participated in the studies, there was a predominance of females (female to male ratio, 26 : 15). The mean age of the patients was ∼35 years, and the number of episodes ranged from 3 to 8 [4, 6, 7]. Parallels in the demographic characteristics of these patient populations, as well as our knowledge of genital herpes, are discussed below.
Demographic characteristics of 13 patients with recurrent benign lymphocytic meningitis.
Demographic characteristics of 14 patients with recurrent benign lymphocytic meningitis.
Demographic characteristics of 14 patients who underwent cytopathologic examination of cerebrospinal fluid samples.
Etiology
In 1991, Yamamoto et al. [8] first reported a case of RBLM attributed to herpes simplex virus (HSV); viral DNA in CSF was detected using PCR. From the available case reports, we determined that RBLM is most frequently caused by HSV-2 and—much less frequently—by HSV-1 [4, 9–17]. Other viruses, such as Epstein-Barr virus, coxsackievirus, and echoviruses, have been implicated as causes of recurrent meningitis; however, data to support this contention have not been rigorously collected [3]. Not all patients have an established pathogenesis. Table 4 summarizes the available data regarding PCR testing of CSF samples of patients with RBLM [6].
Data from viral studies of CSF samples from patients with recurrent benign lymphocytic meningitis (RBLM).
Pathogenesis
HSV-1 usually colonizes the trigeminal ganglia during the latent period, but it can be found in other dorsal root ganglia, as well. In contrast, HSV-2 usually colonizes the sacral sensory ganglia during the latent period [18–20]. The reactivation of HSV-1 results in herpes labialis or, less frequently, in stomatitis, keratoconjunctivitis, or genital herpes. The reactivation of latent HSV-2 results in recurrent genital herpes. For both viruses, reactivation is more frequently associated with asymptomatic infection and viral shedding in the absence of symptoms. It has been postulated that reactivation of HSV causes RBLM [4, 21]. We presume that the same strain of HSV that causes genital herpes also causes RBLM, although genetic mapping by restriction endonuclease analysis of isolates of that strain has not been performed [16].
Diagnosis
The predominant, characteristic CSF abnormality is a lymphocytic pleocytosis. Some investigators have proposed that RBLM is different from Mollaret meningitis, because the former tends to cause initial CSF lymphocytic predominance, and the latter causes initial polymorphonuclear pleocytosis followed by lymphocytic predominance [4]. However, this distinction appears to be irrelevant. The appearance of large granular plasma cells is considered to be the hallmark of Mollaret meningitis [7]. These cells can be demonstrated by Papanicolaou's stain and are usually evident during the first 24 h of the illness, but then they disappear quickly. These large, granular cells have monocytic-macrophage lineage. They may also be absent in CSF. Similar cells have been reported with other viral infections of the CNS (most notably, West Nile virus meningoencephalitis) [22, 23]. Protein levels in CSF are mildly elevated, and the glucose level is usually normal. The CSF cell count and results of blood chemistry tests are comparable to those associated with other aseptic meningitides with a lymphocytic predominance (table 5) [4].
Findings of routine CSF studies in 13 patients with recurrent benign lymphocytic meningitis.
Analysis of CSF by PCR for HSV DNA is considered to be the gold standard for diagnosis. However, other etiologies should additionally be sought at the time of initial patient evaluation. In the study by Tedder et al. [4], 85% of the patients had a result positive for HSV DNA by PCR of their CSF sample. One patient had HSV-1 infection, and 10 patients had HSV-2 infection . In another study, 67% of the patients had results positive for HSV DNA by CSF PCR. Of patients with a positive result, 95% had HSV-2 detected, and 5% had HSV-1 detected [6]. Interestingly, HSV-1 or HSV-2 antibodies were detected in 100% of the patients [4]. The presence of the HSV antibodies in CSF does not confirm the diagnosis, because the blood-brain barrier may be inflamed, which allows HSV antibodies to penetrate the CSF. Culture of the CSF for HSV is usually—and not surprisingly—negative [11, 12, 24–29]. In a series of 12 patients who had 19 different episodes of RBLM, none of the patients had positive CSF viral cultures. These findings are virtually identical to those of patients who have herpes simplex encephalitis confirmed either by brain biopsy or PCR [30].
When PCR assessment of CSF fails to detect HSV DNA, other infectious etiologies should be considered. However, the unequivocal association that has been made between other viral agents and RBLM has historically been made on the basis of ancillary data.
Treatment
Because of the low incidence of RBLM, no placebo-controlled clinical trials have been conducted to assess the efficacies of the currently available therapies for HSV infection. Historically, acyclovir has been used for treatment and suppression of HSV infection [29, 31, 32], and treatment of RBLM is no exception. As the name implies, RBLM is a benign, self-limited illness; however, acyclovir has been administered as therapeutic treatment, as well as for the suppression of recurrences. Some investigators do not think acyclovir therapy alters the natural course of the illness [32].
Administration of intravenous acyclovir (5–10 mg/kg every 8 h for 7–10 days) has putatively resulted in rapid resolution of infection. More recently, because of improved pharmacokinetics, second-generation antiherpetic drugs—valacyclovir and famciclovir—have been shown to be efficacious for the management of genital herpes. Treatment with valacyclovir and famciclovir results in significantly higher concentrations of acyclovir and penciclovir in plasma. Valacyclovir and famciclovir, when metabolized to acyclovir and penciclovir, respectively, penetrate the CSF to a similar extent (i.e., 30% of plasma levels) [22]. Both medications have been used to treat patients with RBLM and, as noted below, to provide long-term suppressive management of infection. Steroids, colchicine, antihistamines, and phenylbutazonum have been administered to patients with RBLM without reported benefit [33, 34]. Indomethacin (25 mg 3 times per day after meals or 50 mg every 4 h) was reported to result in faster recovery and longer symptom-free intervals between episodes [35, 36]. Evidence-based clinical trials that support treatment with any of these adjunctive regimens are not available and, because of the rareness of the disease, they are not likely to be performed. As would be expected, episodic therapy would not likely influence subsequent recurrences.
As in the case of frequently recurrent genital herpes, suppressive oral therapy with acyclovir, valacyclovir or famciclovir has been routinely employed [37, 38]. Similar regimens have been used for the management RBLM. In 1 instance, a 52-year-old woman who experienced 21 episodes of recurrent aseptic meningitis over 20 years began suppressive therapy with acyclovir; no other outbreaks were reported after treatment [21]. Because of the rarity of RBLM, controlled studies that define the correct dosage and actual benefit of treatment are unlikely. Most experts suggest that suppressive antiviral therapy should be offered to individuals who have RBLM.
Conclusions
Importantly, most confirmed cases of RBLM are attributed to HSV-2 infection, which implies concomitant genital infection. The overrepresentation of females in the medical literature parallels the natural history of genital herpes among the population-at-large. Similarly, the lack of a history of genital HSV infection among subjects with RBLM in the literature is not surprising [39]. Regardless of the medical history of those individuals with a diagnosis of HSV-2 RBLM who have been proven to have the illness, counseling about genital herpes and the possibility of transmission of infection should be a component of treatment.
Acknowledgments
Financial support. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services (grants NO1-AI-30025, NO1-AI-65306, and NO1-AI -15113, NO1-AI-62554), the General Clinical Research Unit (grant RR-032), and the State of Alabama.
Potential conflicts of interest. M.S. and R.J.W.: no conflicts.






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