MISCELLANEOUS PAPER

Mollarets meningitis and herpes simplex virus

type 2 infections

P Farazmand MD MRCP*, P D Woolley MBChB FRCP* and G R Kinghorn MD FRCP

*Sexual Health Department, South Manchester University Hospitals, Manchester; Department of Genito-Urinary Medicine,
Royal Hallamshire Hospital, Sheffield, UK

Summary: Benign recurrent aseptic meningitis is a rare disorder described by Mollaret in 1944. When initially described, this
form of aseptic meningitis had no identifiable infecting agent. New sophisticated diagnostic tools have now identified herpes simplex
type 2 virus as the most commonly isolated agent. Antiviral treatment has been used successfully for prophylaxis and treatment.

Keywords: aciclovir, antivirals, genital herpes, herpes simplex, HSV-2, meningitis, Mollaret

In 1944, Pierre Mollaret (18981987), a French physician,
described an aseptic meningitis syndrome characterized by
spontaneously remitting recurrent episodes of severe headache,
stiff neck and fever.1 Classically, cerebrospinal uid (CSF) exam-
ination showed pleocytosis in which large mononuclear cells
(now considered to be monocytes) predominated within 24
hours of episode onset. Symptoms lasted for up to seven days
and full recovery was usual. Atypically, transient neurological
symptoms such as seizures and hallucinations, or signs of
cranial nerve palsies or abnormal reexes, were reported.
The diagnosis is one of exclusion. It has to be differentiated
from other infectious and non-infectious causes of acute
aseptic meningitis. Its characteristic recurrent nature can
also be mimicked by conditions such as Behcets, sar-
coidosis, other autoimmune disorders, or be associated with
medications.
Recent studies in acute aseptic meningitis using polymerase
chain reaction (PCR)-based assays have shown herpes simplex
virus type 2 (HSV-2) and varicella-zoster virus each appear to
cause around 20% cases both in Sweden and in the UK,2,3
while enteroviruses are the most commonly identied agents.
Moreover, herpes viruses are now being implicated as the
most common aetiological agents of recurrent aseptic lympho-
cytic meningitis with HSV-2 being the usual cause, reported in
up to 85% cases.4,5
Both HSV-1 and HSV-2 are neurotropic viruses that can cause
disease by direct CNS invasion and replication. Recurrent
disease results from reactivation of latent infection within
sensory ganglia. In primary genital herpes, symptoms of
meningitis have been reported in 36% women and 11% men,6
of whom around one in six require hospitalization.7
Occasionally, aseptic meningitis may be the sole clinical
Correspondence to: P Farazmand,
Sexual Health Department, Withington Hospital,
Nell Lane, West Didsbury, Manchester M20 2LR, UK
Email: pfarazmand@googlemail.com
presentation of newly acquired HSV-2 infections.8 Localized
CNS involvement due to herpesviruses can also result in a
transverse myelitis or sacral radiculopathy.9
Aurelius et al. 10 retrospectively reviewed the records of 40
consecutive patients with HSV-2 meningitis and/or myeloradi-
culitis. During the year following the acute phase, veried or
suspected neurological recurrences were noted in nearly half
of the patients. Recurring mucocutaneous symptoms were
observed in 16 patients. Eleven patients experienced concurrent
or separate episodes of recurring mucocutaneous and neuro-
logical symptoms, seven had neurological recurrences only
and ve had mucocutaneous recurrences alone.
The likelihood that a rst acute episode of lymphocytic
meningitis would lead to recurrent episodes was determined
in a study of 665 patients treated at the Helsinki University
Central Hospital between 1996 and 2006.11 Of these, 37 (5.6%)
went on to have benign recurrent aseptic meningitis and of
these 28 (76%) had HSV-2 DNA present in the CSF. The preva-
lence of recurrent lymphocytic meningitis associated with
HSV-2 was 2.2/100,000 population. A detailed follow-up of
22 of these patients recorded combined 95 episodes of recurrent
aseptic meningitis; of these, 32% gave no history consistent
with prior orolabial or genital herpetic infection. The presence
of HSV-2 DNA in the CSF was sought in 48 of these episodes
and was found to be positive in 46% taken 24 48 hours after
symptom onset and 82% if sampled during the rst two to
ve days. No HSV-2 DNA was detected if sampled earlier
than 24 hours or later than ve days. CSF abnormalities were
less in recurrent than rst episodes of HSV-2 meningitis with
lower cell counts, protein and higher glucose.
Thus, it appears that at least 20% of those with an initial
episode of HSV-2 meningitis will have a recurrence. The sub-
sequent pattern varies but typically become less frequent with
time. The marked predominance of female cases12 in recurrent
episodes mirrors the different sex ratio of neurological features
in primary genital herpes. Although around half of these epi-
sodes occur in association with mucocutaneous recurrences,
many patients with PCR-conrmed recurrent lymphocytic

International Journal of STD & AIDS 2011; 22: 306 307. DOI: 10.1258/ijsa.2010.010405
 Farazmand et al. Mollarets meningitis and HSV-2 infections
................................................................................................................................................
Table 1 Characteristics of recurrent benign aseptic
lymphocytic (Mollarets) meningitis associated with
herpes simplex virus type 211
(1) Recurrent episodes of meningitis
(2) Episodes separated by symptom-free periods
(3) Spontaneous remission of symptoms
(4) Fever (not always present)
(5) Transient neurological symptoms in 50% of cases
(6) No permanent neurological sequelae
(7) Genital symptoms absent in at least half cases
meningitis caused by HSV-2 do not have a previous history of
genital lesions.
The characteristics of HSV-2 associated recurrent lymphocy-
tic (Mollarets) meningitis are summarized in Table 1. It is
important to emphasize that Mollarets meningitis is a benign
condition, in contrast to HSV encephalitis which is usually
caused by HSV-1 and is not benign.
Treatment with intravenous aciclovir leads to resolution of
symptoms within 48 hours but episodic treatment does not
prevent further episodes. Both oral aciclovir and valaciclovir
in standard suppressive treatment doses have been shown to
effectively prevent further episodes.13,14 The effectiveness of
long-term antiviral therapy, as opposed to episodic treatment,
has been shown in a number of reports. A 53-year-old
woman with more than 21 hospitalizations for benign lympho-
cytic meningitis had remained symptom-free for two years
following the initiation of suppressive oral aciclovir.14 A
44-year-old woman successfully used suppressive oral aciclovir
having attempted, unsuccessfully, to use episodic therapy.15
The advent of widespread PCR testing has highlighted
HSV-2, and not HSV-1, as the predominant cause of recurrent
lymphocytic (Mollarets) meningitis. Neurological recurrences
may be a more common cause of severe debility associated
with genital HSV-2 than is currently recognized, especially as
at least one-third of cases occur in the absence of a history of
genital lesions. Constitutional symptoms may precede or
accompany anogenital lesions in 30% patients, and sciatic neur-
algic pain is also common in those with recurrent genital
herpes. Variable severity of neurological involvement may
explain why some patients are more severely physically inca-
pacitated by recurrent genital herpes.
Accurate diagnosis will also prevent repeated episodes of
prolonged admission, unnecessary investigation and expensive
empirical treatment for other infective causes of meningitis.16
Antiviral treatment appears to be effective both in shortening
307
acute episodes and in preventing recurrence. Hence, a greater
appreciation of HSV-2 infections as a cause of Mollarets menin-
gitis and other neurological conditions should help provide
opportunities for improved disease prevention and patient
management.
REFERENCES
1 Mollaret P. La meningite endothelio-leucocytaire multirecurrente benigne.
Syndrome nouveau ou maladie nouvelle? Documents cliniques. Rev Neurol
1944;76:657 8
2 Franzen-Rohl E, Larsson K, Skoog E, et al. High diagnostic yield by CSF-PCR
for entero- and herpes simplex viruses and TBEV serology in adults with acute
aseptic meningitis in Stockholm. Scand J Infect Dis 2008;40:914 21
3 Ihekwaba UK, Kudesia G, McKendrick MW. Clinical features of viral
meningitis in adults: signicant differences in cerebrospinal uid ndings
among herpes simplex virus, varicella zoster virus, and enterovirus infections.
Clin Infect Dis 2008;47:783 9
4 Bergstrom T. Is Mollarets meningitis caused by herpes simplex virus type 2?
Lakartidningen 1989;86:1279 80
5 Tedder DG, Ashley R, Tayler KL, et al. Herpes simplex virus infections as a
cause of benign recurrent lymphocytic meningitis. Ann Intern Med
1994;121:334 8
6 Tyler KL. Herpes simplex virus infections of the central nervous system:
encephalitis and meningitis, including Mollarets. Herpes 2004;11(Suppl 2):
p57A 64A
7 Corey L, Adams HG, Brown ZA, et al. Genital herpes simplex virus infection:
Clinical manifestations, course and complications. Ann Intern Med
1983;48:958 72
8 Corey L, Wald A. Genital herpes. In: Holmes KK (ed). Sexually Transmitted
Diseases, 4th edn. Chicago: McGraw-Hill, 2008:407
9 Klastersky J, Cappel R, Snoeck J, et al. Ascending myelitis in association with
herpes simplex virus. N Engl J Med 1972;187:182 4
10 Aurelius E, Forsgren M, Gille E, et al. Neurologic morbidity after herpes
simplex virus type2 meningitis: a retrospective study of 40 patients. Scand J
Infect Dis 2002;34:278 83
11 Kallio-Laine K, Seppanen M, Kautiainen H, et al. Recurrent lymphocytic
meningitis positive for herpes simplex virus type 2. Emerg Infect Dis
2009;15:111922
12 Tang YW, Cleavinger PJ, Li H, et al. Analysis of candidate-host
immunogenetic determinants in herpes simplex virus-associated Mollarets
meningitis. Clin Infect Dis 2000;30:176 8
13 Gignoux L, Ryvlin P, Najioullah F, Mauguiere F. Recurrent Mollarets
meningitis of herpetic origin. Presse Med 1998;27:1470 2
14 Mirakhur B, McKenna M. Recurrent herpes simplex type 2 virus (Mollarets
meningitis). J Am Board Fam Pract 2004;17:303 5
15 Sato R, Ayabe M, Shoji H, et al. Herpes simplex virus type 2 recurrent
meningitis (Mollarets meningitis): a consideration for the recurrent
pathogenesis. J Infect 2005;51:e217 20
16 Abu Khattab M, Al Soub H, Al Maslamani M, et al. Herpes simplex virus type
2 (Mollarets) meningitis: a case report. Int J Infect Dis 2009;13:e476 9
(Accepted 29 December 2010)
Copyright of International Journal of STD & AIDS is the property of Royal Society of Medicine Press Limited
and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright
holder's express written permission. However, users may print, download, or email articles for individual use.