The elusive diagnosis: Recurrent benign lymphocytic meningitis
Recurrent benign lymphocytic meningitis (RBLM) or Mollaretmeningitis is a rare disease with a prevalence of 1-2.2/100,000 population. It is characterized by recurrent episodes of aseptic meningitis. The diagnosis is made via history fitting Bruyn's criteria, and confirmatory detection of HSV-2 in cerebrospinal fluid (CSF) via polymerase chain reaction (PCR). A 59-year-old female with a past medical history (PMH) of rheumatoid arthritis in remission and 11 prior episodes of aseptic meningitis presented with sudden and severe headache, photophobia, nausea, vomiting, and meningismus without focal findings. CSF analysis revealed aseptic meningitis with Herpes simplex 2 virus (HSV-2) present by PCR. RBLM remains a rare and elusive diagnosis but PCR technology has made it easier to diagnose. We present a 59-year-old female with classic features of RBLM, now suffering a 12th episode of aseptic meningitis. Heightened awareness of RBLM among clinicians may allow for an earlier diagnosis, reduced use of unnecessary antibiotics, shortened hospitalizations, and lower costs.
volume 77, no. 8 477
e Elusive Diagnosis:
Recurrent Benign Lymphocytic Meningitis
TINE VINDENES, MD, GABRIEL CROWL, AB, BHOOSHAN M PERERA, MD,
AND GARY SCHLEITER, MD
ABSTR ACT — Background: Recurrent benign lym-
phocytic meningitis (RBLM) or Mollaret meningitis
is a rare disease with a prevalence of 1-2.2/100,000
population. It is characterized by recurrent episodes
of aseptic meningitis. e diagnosis is made via
history tting Bruyn’s criteria, and conrmatory
detection of HSV-2 in cerebrospinal uid (CSF) via
polymerase chain reaction (PCR).
Case: A 59-year-old female with a past medical history
(PMH) of rheumatoid arthritis in remission and 11
prior episodes of aseptic meningitis presented with
sudden and severe headache, photophobia, nausea,
vomiting, and meningismus without focal ndings.
CSF analysis revealed aseptic meningitis with Herpes
simplex 2 virus (HSV-2) present by PCR.
Conclusion: RBLM remains a rare and elusive diag-
nosis but PCR technology has made it easier to di-
agnose. We present a 59-year-old female with classic
features of RBLM, now suering a 12th episode of
aseptic meningitis. Heightened awareness of RBLM
among clinicians may allow for an earlier diagnosis,
reduced use of unnecessary antibiotics, shortened
hospitalizations, and lower costs.
-- female with a past medical history
of rheumatoid arthritis in remission, and 11
episodes of aseptic meningitis — all of which
had required hospitalization and were assumed to be of
viral origin — presented with headache, photophobia,
nausea, vomiting, neck stiness, and a low-grade fever.
Her headache was described as sudden in its onset and
severe, localized to the frontal area of her head without
aggravating or ameliorating factors. She denied any
recent upper respiratory tract infection, facial pain,
rash, diarrhea, seizures, known tick bites, sick contacts,
or recent travel. She reported no history of sexually
transmitted disease, specically including no recollec-
tion of any genital herpes outbreak. e patient stated
that her prior episodes of aseptic meningitis had been
similar to this in presentation and were characterized by
symptoms lasting seven or eight days, resolving without
sequelae. No specic etiology had ever been conrmed
despite having undergone numerous lumbar punctures
at the time symptoms were present. Her rst episode
occurred about 20 years ago and was particularly severe.
On examination, the patient had an oral temperature
of 37.9° C, blood pressure of 112/62 mmHg, a heart
rate of 92 beats per minute, and a respiratory rate of 14
per minute. ere were ndings of neck stiness with
positive Brudzinski and Kernig signs; moreover, she
was fully alert and oriented and there were no focal
neurological ndings. ere were no signs of ulcer-
ation or lesions on mucosal surfaces or skin, including
the genital area. A CT of the head demonstrated no
evidence of an acute intracranial abnormality. Labora-
tory studies, including complete blood count, serum
electrolytes, blood urea nitrogen, and creatinine, proved
unremarkable. Her serum leukocyte count was normal
(7,500 per cubic millimeter)and serum glucose was 123
mg/dL. e cerebrospinal uid (CSF) demonstrated
elevated total protein and white cell count (with leuco-
TINE VINDENES, MD, BHOOSHAN M PERERA, MD,
Western Connecticut Health Network (WCHN), Department
of Internal Medicine,Danbury Hospital, Danbury; GABRIEL
CROWL, AB, University of Vermont College of Medicine,
Burlington, VT; GARY SCHLEITER, MD, Western Con-
necticut Health Group (WCHG), Department of Infectious
Diseases, Danbury; Corresponding author: TINE VINDENES,
connecticut medicine, september 2013
cytosis and monocytosis)
(Table 1). e Gram stain
and CSF cultures were
negative, and there were
no fungal organisms by
India ink staining. Her
CSF was also negative for
polymerase chain reac-
tion (PCR) of Borrelia,
Enterovirus, and Varicella
Zoster virus, but did prove
positive for Herpes sim-
plex 2 virus (HSV-2) by
PCR. West Nile serology
was negative. Similarly, the patient was seronegative
for antibodies to ds-DNA, histones, Smith antigen,
ribonucleoproteins, DNA topoisomerase I, centromeric
proteins, and histidyl-tRNA synthetase. ere was a
positive titer for generic antinuclear antibodies (1:80).
e patient was initially treated empirically with
ceftriaxone for the possibility of bacterial meningitis,
but this was discontinued once the CSF results were
available, based upon strong clinical suspicion for aseptic
meningitis. Given the severe clinical presentation, antivi-
ral treatment was begun on the second hospital day with
intravenous acyclovir, 800 mg three times daily. Her CSF
was conrmed positive for HSV-2 by PCR on the third
hospital day. She was afebrile after the rst hospital day;
however, her severe headache requiring intravenous pain
medication persisted for several days. Her hospital course
was complicated by a minor lower extremity cellulitis, but
she was discharged after an eight-day stay, and returned
to her normal state of health. She was not sent home on
suppressive antiviral medications.
Recurrent benign lymphocytic meningitis (RBLM) or
Mollaret meningitis is a rare disease. e prevalence of
HSV-2 associated RBLM is estimated to be 1-2.2/100
with a female predominance
female to male ratio of 1.7:1.
RBLM was discovered
by the French neurologist Pierre Mollaret in 1944 who,
after diagnosing three patients with RBLM, named the
disease Mollaret meningitis.
RBLM is characterized by recurrent episodes of
aseptic meningitis, as few as three episodes to at least 10
episodes, and lasting two to ve days followed by spon-
with symptom-free periods lasting
months to years with a median of 47 months (range of
one to 216 months) between the rst and second episodes
e episodes are typically acute in onset and associ-
ated with severe headache, fever, photophobia, and
meningeal signs. About
50% of the patients have
signs including seizures,
nerve palsies, and altered
The first RBLM case
attributed to HSV-2 was
reported by Yamamoto et
al in 1991
was utilized to detect
HSV-2 in CSF. RBLM is
largely caused by HSV-2,
but may rarely be caused by HSV-1
and other viruses
such as Epstein Barr virus (EBV), Coxsackie virus, and
Echovirus. However, data is missing to secure Epstein
Barr virus, Coxsackie virus, and Echovirus as a certain
cause for recurrent benign lymphocytic meningitis.
Among the noninfectious causes of recurrent aseptic
meningitis are Becet’s and Vogt Koyanagi-Harada syn-
dromes, sarcoidosis, systemic lupus erythematosus, and
adverse reactions to chemicals in wood preservatives;
moreover, intracerebral and pineal cysts
have been as-
sociated with Mollaret meningitis.
Herpes simplex virus (HSV) is a neurotropic virus
whose name originates from ancient Greek and translates
“to creep or crawl.”
HSV-2 establishes latency mainly in
sensory neurons of the sacral root ganglia and typically
causes mucocutaneous disease upon reactivation. None-
theless, most patients with Mollaret’s meningitis do not
report active skin lesions at the onset of their illness and
many have no prior knowledge of a genital infection.
activation is more frequently associated with asymptomatic
infection and viral shedding in the absence of symptoms.
It has been postulated that reactivation of HSV causes
and presumed 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.
The diagnosis of Mollaret meningitis used to be
accomplished by fullling Bruyn’s criteria
Nowadays, the clinical characteristics of Bruyn’s criteria
are used together with the laboratory diagnosis, secured
by analyzing the CSF which typically demonstrates
mildly elevated protein levels and normal glucose levels
with a lymphocytic predominance and large granular
plasma cells, known as Mollaret cells, evident in the rst
24 hours of the illness.
As PCR is extremely sensitive
and highly specic for the diagnosis of HSV infections
in the central nervous system (CNS),
the analysis of
CSF by PCR for HSV DNA is now considered the gold
standard for diagnosis.
Table 1. Case cerebrospinal uid (CSF) ndings
Patient Value Reference Value
Appearance colorless colorless
Total protein (mg/dL)
Glucose (mg/dL) 54 50-75
Red blood cells/mm
White blood cells/mm
volume 77, no. 8 479
HSV-1 or HSV-2 antibodies were detected in 100%
of the patients in a Tedder et al study,
but the presence
of the HSV antibodies in CSF does not conrm the
diagnosis as the blood-brain barrier may be inamed al-
lowing HSV antibodies to penetrate the CSF. Further-
more, culture of the CSF for HSV is usually negative.
Treatment of RBLM is not standardized. RBLM,
being a low-incidence disease, has not been assessed by
placebo-controlled clinical trials to study the ecacy
of currently available therapies. Historically, acyclovir
has been used for the treatment and suppression of
HSV infection and the same logic has been extended to
RBLM. Administration of intravenous acyclovir (5–10
mg/kg every eight hours for seven to 10 days) results
in rapid resolution. Treatments with valacyclovir and
famciclovir have been used to treat patients with RBLM
and to provide long-term suppressive management of
infection. Indomethacin (25 mg three times per day
after meals or 50 mg every four hours) was reported
to result in faster recovery and longer symptom-free
intervals between episodes.
In cases of frequently
recurring genital herpes, suppressive oral therapy with
acyclovir, valacyclovir, or famciclovir has been routinely
and similar regimens have been used for
the management of RBLM with good results.
to the rarity of RBLM, future controlled studies that
dene the correct dosage and actual benet of treat-
ment are unlikely. Most experts suggest that suppressive
antiviral therapy should be oered to individuals who
Recurrent benign lymphocytic meningitis remains a
rare and elusive diagnosis, but the widespread availability
of PCR testing for HSV-2 in CSF has enhanced our
ability to diagnose this entity. We present a 59-year-old
female with the classic features of RBLM, now suering
a 12th episode of aseptic meningitis over a period of 20
years. Until this admission her aiction had gone un-
diagnosed. e possibility of HSV-2 associated RBLM
should be explored in any patient with recurrent aseptic
meningitis. e diagnosis is easily made via history t-
ting Bruyn’s criteria, supported by LP with CSF analysis,
and conrmed by HSV PCR. Heightened awareness of
RBLM among clinicians will result in earlier diagnosis,
reduced use of unnecessary antibiotics, shortened
hospitalizations, and lower costs.
1. Jensenius M, Myrvang B, Storvold G, et al. Herpes
simplex virus type 2 DNA detected in cerebrospinal fluid
of 9 patients with Mollaret’s meningitis. Acta Neurol Scand.
2. Kallio-Laine K, Seppänen M, Kautiainen H, et al. Re-
current lymphocytic meningitis positive for herpes simplex
virus type 2. Emerg Infect Dis. 2009 Jul;15(7):1119-22.
3. Tang YW, Cleavinger PJ, Li H, Michell PS, et al. Persisting
DH Analysis of candidate-host immunogenetic determinants
in herpes simplex virus associated Mollaret’s meningitis. Clin
Infect Dis. 2000 Jan;30(1):176-80: 176-178.
4. Chan TY, Parwani AV, Levi AW, et al. Mollaret’s meningitis:
cytopathologicanalysis of fourteen cases. Diagn Cytopathol.
5. Tedder DG, Ashley R, Tyler KL, et al:. Herpes simplex virus
infection as a cause of benign recurrent lymphocytic meningitis.
Ann Intern Med. 1994;121(5):334-8.
6. Kupila L, Vainionpaa R, Vuorinen T, et al. Recurrent lympho-
cytic meningitis: the role of herpes viruses. Arch Neurol. 2004
7. Mollaret P. La meningite endothelio-leukocytaire multi-
recurrente benigne. Rev Neurol. 1977 Apr;133(4):225-44.
8. Galdi AP. Benign recurrent aseptic meningitis (Mollaret’s
meningitis): case report and clinical review. Arch Neurol. 1979
9. ShalabiM, Whitley RJ. Recurrent benign lymphocytic men-
ingitis. Clin Infect Dis. 2006;43(9):1194-7.
10. Yamamoto LJ, Tedder DG, Ashley R et al. Herpes simplex
virus type 1 DNA in cerebrospinal fluid of a patient with
Mollaret’s meningitis. New Engl J Med. 1991;325(15):1082-5.
11. Aristegui FJ, Delegado RA, Olega ZL et al: Mollaret’s recurrent
aseptic meningitis and cerebral epidemioid cyst. Pedr Neurol.
12. Dylewski JS, Bekhor S. Mollaret’s meningitis caused by herpes
simplex virus type 2: case report and literature review. Eur J
Clan Micobiol Infect Dis. 2004 Jul;23(7):560-2
13. Roizman B, Whitley RJ. The nine ages of herpes simplex
virus. Herpes. 2001;8:23–27.
14. Mirakhur B, McKenna M. Recurrent herpes simplex type
2 virus (Mollaret) meningitis. J Am Board Fam Pract. 2004
15. Venot C, Beby A, Bourgoin A et al: Genital recurrent infection
occurring 6 months after meningitis due to the same herpes
simplex virus type 2 (HSV-2) strain evidence by restriction
endonuclease analysis. J Infect. 1998 Mar;36(2):233-5.
16. Bruyn G, Straathof J, Raymakers G. Mollaret’s meningitis:
differential diagnosis and diagnostic pitfalls. Neurology. 1962
17. Wynants H, Taelman H, Martin JJ et al. Recurring aseptic
meningitis after travel to the tropics: a case of Mollaret’s
meningitis? Case report with review of the literature. Clin
Neurol Neurosurg. 2000 Jun;102(2):113-5.
18. Ikari H, Kuzuya M, Yoshimine N et al: A case of indomethacin-
inhibited recurrent periodical attacks of Mollaret’s meningitis.
Nippon Ronen Igakkai Zasshi. 1993 Mar;30(3):216-21.
19. Mertz GJ, Loveless MO, Levin MJ, et al. Oral famciclovir for
suppression of recurrent genital herpes simplex virus infection
in women: a multicenter, double-blind, placebo-controlled trial.
Collaborative Famciclovir Genital Herpes Research Group.
Arch Intern Med. 1997;157(3):343-9.
Table 2. Bruyn’s clinical criteria for Mollaret meningitis
• Recurrent attacks of severe headache, meningismus, and fever
• Attacks separated by symptom-free intervals of weeks to months
• Spontaneous abeyance of symptoms and signs after several days
• No permanent sequelae