The elusive diagnosis: Recurrent benign lymphocytic meningitis

Article (PDF Available)inConnecticut medicine 77(8):477-9 · September 2013with12 Reads
Source: PubMed
Abstract
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 suering 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.
A
-- 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, specically 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 specic etiology had ever been conrmed
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,
MD, tinevindenes@gmail.com.
connecticut medicine, september 2013
478
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 conrmed 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.
Discussion
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
000 population
1,2
with a female predominance
3
and a
female to male ratio of 1.7:1.
4,5,6
RBLM was discovered
by the French neurologist Pierre Mollaret in 1944 who,
after diagnosing three patients with RBLM, named the
disease Mollaret meningitis.
2
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-
taneous recovery
7,8
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
of meningitis.
2
e episodes are typically acute in onset and associ-
ated with severe headache, fever, photophobia, and
meningeal signs. About
50% of the patients have
transient neurological
signs including seizures,
hallucinations, diplopia,
nerve palsies, and altered
mental status.
9
The first RBLM case
attributed to HSV-2 was
reported by Yamamoto et
al in 1991
10
where PCR
was utilized to detect
HSV-2 in CSF. RBLM is
largely caused by HSV-2,
but may rarely be caused by HSV-1
9
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.
8
Among the noninfectious causes of recurrent aseptic
meningitis are Becets and Vogt Koyanagi-Harada syn-
dromes, sarcoidosis, systemic lupus erythematosus, and
adverse reactions to chemicals in wood preservatives;
moreover, intracerebral and pineal cysts
11
have been as-
sociated with Mollaret meningitis.
12
Herpes simplex virus (HSV) is a neurotropic virus
whose name originates from ancient Greek and translates
“to creep or crawl.
13
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 Mollarets meningitis do not
report active skin lesions at the onset of their illness and
many have no prior knowledge of a genital infection.
12
Re-
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
RBLM
5,14
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.
15
The diagnosis of Mollaret meningitis used to be
accomplished by fullling Bruyn’s criteria
16
(Table 2).
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
5
with a lymphocytic predominance and large granular
plasma cells, known as Mollaret cells, evident in the rst
24 hours of the illness.
4
As PCR is extremely sensitive
and highly specic for the diagnosis of HSV infections
in the central nervous system (CNS),
5
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)
134 15-40
Glucose (mg/dL) 54 50-75
Red blood cells/mm
3
5 <6
White blood cells/mm
3
195 <6
lymphocytes
netrophils
monocytes
68%
11%
21%
>50%
none
none
volume 77, no. 8 479
HSV-1 or HSV-2 antibodies were detected in 100%
of the patients in a Tedder et al study,
5
but the presence
of the HSV antibodies in CSF does not conrm the
diagnosis as the blood-brain barrier may be inamed 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 ecacy
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.
17,18
In cases of frequently
recurring genital herpes, suppressive oral therapy with
acyclovir, valacyclovir, or famciclovir has been routinely
employed
18,19
and similar regimens have been used for
the management of RBLM with good results.
14
Due
to the rarity of RBLM, future controlled studies that
dene the correct dosage and actual benet of treat-
ment are unlikely. Most experts suggest that suppressive
antiviral therapy should be oered to individuals who
have RBLM.
Conclusion
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 aiction 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.
REFERENCES
1. Jensenius M, Myrvang B, Storvold G, et al. Herpes
simplex virus type 2 DNA detected in cerebrospinal fluid
of 9 patients with Mollarets meningitis. Acta Neurol Scand.
1998;98:209–12.
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 Mollarets meningitis. Clin
Infect Dis. 2000 Jan;30(1):176-80: 176-178.
4. Chan TY, Parwani AV, Levi AW, et al. Mollarets meningitis:
cytopathologicanalysis of fourteen cases. Diagn Cytopathol.
2003 May;28(5):227-31.
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
Oct;61(10):1553-7.
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 (Mollarets
meningitis): case report and clinical review. Arch Neurol. 1979
Oct;36(10):657-8.
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
Mollarets meningitis. New Engl J Med. 1991;325(15):1082-5.
11. Aristegui FJ, Delegado RA, Olega ZL et al: Mollarets recurrent
aseptic meningitis and cerebral epidemioid cyst. Pedr Neurol.
1998 Feb;18(2):156-9.
12. Dylewski JS, Bekhor S. Mollarets 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
Jul-Aug;17(4):303-5.
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. Mollarets meningitis:
differential diagnosis and diagnostic pitfalls. Neurology. 1962
Nov;12:745-53.
17. Wynants H, Taelman H, Martin JJ et al. Recurring aseptic
meningitis after travel to the tropics: a case of Mollarets
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 Mollarets 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. Bruyns 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
  • Article · Dec 1962
  • [Show abstract] [Hide abstract] ABSTRACT: To identify the role of herpes simplex virus (HSV) in causing benign recurrent lymphocytic meningitis. Prospective cohort study. Tertiary referral center. 20 consecutive patients with a provisional diagnosis of benign recurrent lymphocytic meningitis had cerebrospinal fluid specimens submitted between 1990 and 1993 to the diagnostic virology laboratory. Thirteen patients met our criteria for benign recurrent lymphocytic meningitis. Herpes simplex virus DNA was detected in cerebrospinal fluid specimens using the polymerase chain reaction, followed by hybridization with a HSV-specific DNA probe. Herpes simplex virus type 1 and type 2 DNA products were distinguished by digestion with restriction enzymes and analysis by gel electrophoresis. Anti-HSV antibodies in cerebrospinal fluid were detected by immunoblot. The patients had 3 to 9 attacks (mean, 4.6 attacks) of benign recurrent lymphocytic meningitis during periods ranging from 2 to 21 years (mean, 8.4 years). Three of 13 patients had known recurrent genital herpes. Cerebrospinal fluid analysis showed 48 to 1600 cells/microL, glucose levels of more than 2.22 mmol/L (40 mg/dL), and protein levels of 41 to 240 mg/dL (0.41 to 2.4 g/L). Herpes simplex virus DNA and anti-HSV antibodies were detected in cerebrospinal fluid samples in 11 of 13 patients (84.6%; 95% CI, 55% to 98%). Ten of these 11 patients had HSV type 2 DNA and HSV type 2 antibodies. One patient had HSV type 1 DNA and HSV type 1 antibodies in the cerebrospinal fluid. The remaining two patients had only anti-HSV type 2 antibodies. Herpes simplex virus, predominantly HSV type 2, was the major agent causing benign recurrent lymphocytic meningitis that met our specified diagnostic criteria.
    Full-text · Article · Oct 1994
  • [Show abstract] [Hide abstract] ABSTRACT: Benign recurrent aseptic meningitis (Mollaret's meningitis) is rare. Only five cases have been reported in this country. This article reports another case and briefly reviews the characteristic manifestations of this disorder.
    Article · Nov 1979
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