Definition

This is a form of benign, recurrent, aseptic meningitis.
It was first described by Pierre Mollaret (1898-1987) in 1944 and he wrote several papers on the condition until 1968.¹

Diagnostic criteria

G W Bruyn (a Dutch neurologist, co-editor of the Handbook of Clinical Neurology series, the most comprehensive source of information in neurology) refined the clinical diagnostic criteria in 1962:²

• Recurrent episodes of severe headache, meningismus and fever.
• Cerebrospinal fluid (CSF) pleocytosis with large 'endothelial' cells, neutrophils and lymphocytes.
• Attacks separated by symptom-free periods of weeks to months.
• Spontaneous remission of symptoms and signs.
• No causative aetiological agent identified.

Pathogenesis

• In recent years there has been increasing evidence to implicate the herpes simplex virus 2 (HSV-2) in many cases - the usual cause of genital herpes - but, also, the herpes simplex virus 1 (HSV-1) - the usual cause of oral herpes.^3,4
• The Epstein-Barr virus has also been implicated, also a human herpes virus.⁵

It has been suggested that if the strict criteria above are followed, these cases should be excluded, and the term Mollaret's meningitis reserved for true idiopathic cases. However, this appears not to be rigorously applied.

Epidemiology

It is very rare and the literature is very limited.

Presentation

• There is a rapid onset of symptoms that are typical of meningitis.
  These are:
  • Fever
  • Headache
  • Neck stiffness
• The symptoms last between 1 and 7 days.
• Symptoms resolve without any residual defect.
• Symptom-free periods may last from weeks to years, but the characteristic feature of this disease is the tendency to recur.
• The clinical picture can be variable.
  • Some have been reported without fever, with transient neurological signs and symptoms, and with raised gammaglobulin in the CSF
  • More severe cases can occur with neurological abnormalities, including seizures, diplopia, abnormal reflexes, cranial nerve palsy, hallucinations and coma
  • This may occur in as many as half of all patients, but full recovery is usual

Investigations

Head CT or MRI scanning is done before lumbar puncture if a brain mass is suspected, e.g. from focal neurological signs or papilloedema.

• The classical feature is the appearance of the CSF:^6,7
  • Mollaret cells are seen, but they are not regarded as pathognomonic
  • They may represent 60 to 70% of all cells in the CSF, but are often seen for only the first 24 hours
  • The evidence suggests that these cells are monocytes
• After the first 24 hours the cells are predominantly lymphocytes, numbering fewer than 3,000 mm³.
• In about a third of cases the CSF glucose is low.
• Other causes of meningitis should be excluded.

Differential diagnosis

Other acute aseptic meningitis:⁸

• Viral - enteroviruses (poliomyelitis, Coxsackievirus, echovirus), herpes simplex virus 1 (HSV-I) and herpes simplex virus 2 (HSV-2), varicella-zoster virus, adenovirus, Epstein-Barr virus, lymphocytic choriomeningitis virus (LCMV), human immunodeficiency virus (HIV), and influenza A and B viruses.
• Bacterial - partially treated meningitis, parameningeal infection, endocarditis, mycoplasma, tuberculosis, ehrlichiosis, borrelia, syphilis, and brucella.
• Fungi.
• Parasites - toxoplasma and cysticercosis.
• Noninfectious:
  • Drugs - non-steroidal anti-inflammatory drugs, co-trimoxazole, amoxicillin, azathioprine, high-dose intravenous immunoglobulin, isoniazid, intrathecal methotrexate and cystine arabinoside, vaccination, allopurinol
  • Systemic disease - sarcoidosis, leptomeningeal cancer, systemic lupus erythematosus (SLE), Wegener's granulomatosis, Behçet's disease, post transplantation, lymphoproliferative disorder, Vogt-Koyanagi-Harada syndrome
  • Miscellaneous - arachnoiditis, migraine, postinfectious syndrome
  • Small, recurrent bleeds of subarachnoid haemorrhage
• Of the above, causes of recurrent meningitis include Behçet's disease, Vogt-Koyanagi-Harada syndrome, sarcoidosis, SLE, and undiagnosed viral, e.g. encephalomyocarditis

Management

• Pain and temperature should be treated in the usual way.
• Intravenous fluid may be required.
• Colchicine and indometacin have been used and clinical observation suggests effectiveness.⁹
• Randomised controlled trials on the the use of antiviral agents are lacking. (This is probably because the disease is so rare that it is impossible to get even a small series.)
• Most sources advocate the use of acyclovir, given the high prevalence of herpes simplex virus (HSV) on polymerase chain reaction testing.^8,10

Prognosis

• Herpes simplex encephalitis is a rare but very serious condition with a mortality around 70% that usually leaves survivors with neurological deficits.
• This is in contrast to Mollaret's meningitis that may be recurrent and unpleasant in the acute attack but does not leave residual damage.

Document references

1. Mollaret P, Cateigne G; A special type of benign endothelio-leukocytic meningitis with multiple recurrences and with synchronous inflammation of the parotid glands; isolation of an ultravirus from chick embryos. Bull Mem Soc Med Hop Paris. 1952 Jul 4-11;68(24-25):946-54.
2. Bruyn GW, Straathof LJ, Raymakers GM; Mollaret's meningitis. Differential diagnosis and diagnostic pitfalls. Neurology. 1962 Nov;12:745-53.
3. 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. 1998 Sep;98(3):209-12. [abstract]
4. Achard JM, Duverlie G, Schmit JL, et al; Mollaret's meningitis and herpes simplex virus type 1. N Engl J Med. 1992 Mar 26;326(13):893-4.
5. Graman PS; Mollaret's meningitis associated with acute Epstein-Barr virus mononucleosis. Arch Neurol. 1987 Nov;44(11):1204-5. [abstract]
6. Stoppe G, Stark E, Patzold U; Mollaret's meningitis: CSF-immunocytological examinations. J Neurol. 1987 Feb;234(2):103-6. [abstract]
7. Lowe E; Mollaret's meningitis: a case report. Acta Cytol. 1982 May-Jun;26(3):338-40. [abstract]
8. MERCK manual. Aseptic meningitis.; Last updated November 2005
9. 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. [abstract]
10. Tyler KL; Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's. Herpes. 2004 Jun;11 Suppl 2:57A-64A. [abstract]

Internet and further reading

• Mollaret's meningitis (www.whonamedit.com)
• Pritz T; Herpes Simplex Encephalitis, eMedicine, Jan 2010

Acknowledgements