A SELF-TEST IM BOARD REVIEW DAVID L LONGWORTH, MD, JAMES K. STOLLER, MD, EDITORS ON A DAVID Z. CHANG, MD, PHD PARVINDER KHURANA, MD ALAN J. TAEGE, MD CLINICAL Department of Internal Medicine, Department of Internal Medicine, Department of Infectious Disease, Cleveland Clinic Cleveland Clinic Cleveland Clinic CASE NATALIE G. CORREIA, DO RALPH J. TUTHILL, MD Department of General Internal Medicine, Department of Anatomic Pathology, Cleveland Clinic Cleveland Clinic

A 35-year'old man with recurrent aseptic

35-YEAR-OLD, previously healthy white or purpuric lesions. The chest, heart, lungs, man presented to the emergency and abdomen are within normal limits. department because of severe , nau- sea, vomiting, , neck stiffness, Diagnostic tests and (temperature 104°F—40°C), which analysis. A lumbar had begun 1 day previously. He stated that he puncture was performed in the emergency had not experienced visual changes, rash, or room. The cerebrospinal fluid was turbid with trauma. In addition, he had not recently trav- the following values: eled or come into contact with anyone known • Red blood cells 68/pL (normal 0-1) to have tuberculosis, and he had no known • White blood cells 385/juL (normal 0-3); risk factors for human immunodeficiency lymphocytes 68%, monocytes 27%, neu- . trophils 1% The patient had experienced two similar • Gram stain: no organisms found episodes during :he preceding 12 months. He • Protein 164 mg/dL (normal 20-50) was treated both times with a brief course of • 45 mg/dL (normal 50-75) intravenous pending cerebrospinal • Tests for infective organisms: all negative, Tests for fluid cultures and thereafter for symptom including the following: virus infectious relief. After each episode, he recovered with- type 1 and type 2 DNA polymerase chain out residual neurologic deficits or other seque- reaction, cryptococcal antigen, fungal serolo- organisms were lae. Routine bacterial cultures of the cere- gy, serology, culture for acid-fast negative brospinal fluid and a culture for bacilli, rapid plasma reagin test for , were performed, but no specific cause was ever and HIV screening. found. Magnetic resonance imaging of the with and without gadolinium contrast was • PHYSICAL EXAMINATION consistent with acute and chronic sinusitis but was otherwise negative. The patient has the room darkened, saying he has a headache and cannot stand the light. Another spontaneous resolution His vital signs are: The patient was initially treated with a course • Temperature 37.8°C (100.0T) of intravenous ceftriaxone pending cere- • Pulse 64 brospinal fluid culture results. The antibiotics • Blood pressure 131/58 mm Hg. were discontinued on the fourth hospital day On examination, the patient has nuchal when the results showed only Staphylococcus rigidity, and any movement of his neck wors- epidermidis, which was thought to be a conta- ens the pain. There are no cranial nerve minant on the basis of the clinical picture. The deficits. The motor and sensory examinations persistent headache was treated symptomati- are unremarkable. Deep tendon reflexes are cally. The nuchal rigidity gradually resolved 2+ and symmetric without evidence of the and the patient was subsequently discharged. Babinski sign. The Kernig and Brudzinski During a follow-up evaluation, there was no signs are not present. There are no petechial evidence of neurologic sequelae.

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Although Behcet syndrome and sar- • • . » coidosis are associated with aseptic meningi- • i . 3 * ± tis, they rarely involve the central nervous sys- tem without also causing systemic signs and symptoms. Both require careful evaluation, including an ophthalmologic examination, for evidence of systemic disease. Fungal are more likely to pro- duce chronic rather than intermittent symp- toms. Fungal cultures and stains are frequent- ly negative, making serology more useful. Aseptic and Mollaret meningitis (also called benign recurrent asep- tic meningitis) are possible causes. Mollaret meningitis is difficult to differentiate from viral meningitides. However, the former is characterized by recurrent episodes of menin- » gitis with symptom-free intervals, which is consistent with the patient's history. Thus, it is the most likely cause.

• A CLOSER LOOK AT A RARE DISEASE

Mollaret meningitis is a rare syndrome with , / characteristic features first described by Mollaret » in 1944.' A 1972 literature review reported fewer than 30 cases worldwide.2 Since then, sev- eral additional cases have been reported.3-13

Signs and symptoms Sudden onset of meningeal signs and symp- toms and rapid resolution without neurologic FIGURE 1. ThinPrep slides of the patient's cerebrospinal sequelae characterize Mollaret meningitis. fluid. Top, numerous monocytoid Mollaret cells with deli- Patients present with recurrent attacks of cate attenuated cytoplasm are present. Papanicolaou stain, meningismus that are sudden in onset and last x 200. Bottom, Mollaret cells have irregularly shaped nuclei. from 1 to 7 days. Fever is generally present, The nuclear diameter is often narrow at one end and wide although severa. patients were afebrile in at the opposite end. Papanicolaou stain, x 400. reported cases.4 , arthralgia, myalgia, nausea, and DIFFERENTIAL DIAGNOSIS vomiting are common. Approximately 50% of patients have transient signs and symptoms What is the most likely cause of this related to the attack on the central nervous 1 patient's symptoms? system.8 These include , hallucina- tions, coma, vertigo, syncope, speech abnor- • Aseptic viral meningitis malities, anisocoria, seventh nerve paresis, • Fungal decreased deep tendon reflexes, Babinski sign, • • Mollaret meningitis and paresis. All signs and symptoms disappear • Sarcoidosis within 24 to 96 hours, and the patient feels Behcet syndrome entirely well until the next episode. The dis- ease never leaves any residual neurologic or The differential diagnosis includes causes of systemic signs or symptoms. culture-negative meningitis. The attacks occur irregularly, and the

200 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 3 MARCH 2001 Downloaded from www.ccjm.org on October 9, 2021. For personal use only. All other uses require permission. symptom-free intervals last from weeks to TABLE 1 years. It is not possible to predict which attack Differential diagnosis will be the last: the disorder generally persists of Mollaret meningitis for 3 to 5 years but has been reported to per- sist as long as 20 years, during which the Infections patient may experience 30 or more separate Idiopathic recurrent bacterial meningitis attacks of . Brain, spinal, or cranial epidural Viral meningitis Cerebrospinal fluid features and other fungal infections During attacks, the cerebrospinal fluid is Brucellosis under increased pressure and has an elevated Tuberculosis count, increased protein con- Cerebral hydatid cyst tent, and a glucose level usually in the low-to- normal range with occasional hypoglycor- Defective immune mechanisms rhachia. Hypoimmunoglobulinemia Mollaret cells. The most distinctive fea- Sickle cell anemia ture of the cerebrospinal fluid is the presence Chronic lymphocytic leukemia of numerous large monocytoid cells called Multiple myeloma Mollaret cells. These have a prominent cyto- Lymphocytic lymphosarcoma erythematosus plasm and large irregular nuclei (FIGURE 1). The Splenectomy cytoplasm is delicate and easily distorted when placed on a slide for microscopy. The Intracranial and intraspinal tumors nuclei are characteristically broad at one end Cerebral hemangioma and narrow at the opposite end. (On air-dried Ependymoma preparations, the broad end may exhibit toe- Craniopharyngioma like projections. This latter change is not seen Glioblastoma on fluid ThinPrep slides.) Mollaret cells read- Intraspinal tumors ily degenerate and disappear from the cere- Intracranial epidermoid tumor In Mollaret brospinal fluid and are rarely seen 18 to 24 Congenital conditions meningitis, hours after the onset of an attack, most likely Myelomeningocele because the cytoplasm is so delicate. Midline cranial or spinal dermal sinus symptom-free Mollaret initially considered the cells to Petrous fistula intervals last be derived from and called them Neurenteric cysts "endothelial leukocytes." However, they are weeks to years Other now considered to be blood-derived mono- Sarcoidosis cytes. If the diagnosis is suspected, cere- Behcet syndrome brospinal fluid cytology should be ordered and Vogt-Koyanagi syndrome the reviewing pathologist should be informed. Harada syndrome Familial Mediterranean fever Diagnosis Whipple disease

The diagnosis of Mollaret meningitis requires ADAPTED FROM HERMANS PE, GOLDSTEIN NP, WELLMAN WE. exclusion of other conditions that may have MOLLARET'S MENINGITIS AND DIFFERENTIAL DIAGNOSIS OF RECURRENT MENINGITIS: REPORT OF CASE, WITH REVIEW OF THE similar clinical presentations (TABLE 1). LITERATURE. AM J MED 1970; 52:128-140. In our patient, the diagnosis of Mollaret meningitis was based on several factors: • The characteristic clinical presentation was consistent with viral meningitis revealed Mollaret cells • No could be identified Bryun et al14 established the following • There was no evidence to support the diagnostic criteria for Mollaret meningitis: diagnosis of other conditions that might • Recurrent attacks of fever associated with produce a similar clinical picture signs and symptoms of meningeal irrita- • Examination of the cerebrospinal fluid tion

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• Attacks separated by symptom-free inter- • Colchicine vals lasting for weeks to months • Treatment of symptoms • Cerebrospinal fluid pleocytosis of mixed • None of the above type including endothelial cells, leuko- cytes, and lymphocytes during attacks There is no specific therapy for this disease. • Periods of remission without residual signs Various antibiotics and antihistamines have • No causative organism detectable. been tried but did not alter the natural course Goldi5 suggested the following amend- of the disorder. Colchicine has been tried ments to Bryun's original criteria: because of the similarity between Mollaret • Fever may be absent meningitis and familial Mediterranean fever • Approximately 50% of patients have tran- and because it has been reported to decrease sient neurologic symptoms or signs in the severity and frequency of attacks. addition to meningeal irritation More recently, it has been suggested that • The symptom-free intervals may vary patients with frequent attacks may benefit from a few days to years from prophylactic acyclovir, which is effective • There may be increased gamma globulin in preventing clinically apparent recurrent fraction in the cerebrospinal fluid. bouts of infection.13 In one reported case the number of episodes Possible causes of Mollaret meningitis decreased after corticosteroid treatment."1 Mollaret meningitis has generally been con- We started our patient on acyclovir 400 sidered a disease of unknown cause. In some mg twice daily. He has been followed by the reports, epidermoid tumors leaked contents infectious disease clinic for 18 months, and that were capable of inducing an inflammato- has been doing well without further episodes ry response, suggesting that this might be a of meningitis at the time of this writing. We cause of Mollaret meningitis.3-15-16 Viral cau- plan to continue acyclovir for 2 years, though sation has also been considered since the orig- this plan is not based on specific data. inal characterization of Mollaret meningitis. Mollaret himself isolated an "ultravirus" in a • PROGNOSIS Long-term case he reported.1? prognosis: Nordbring and Gertzen18 postulated that Although acute episodes can cause disabling herpes simplex virus is a cause of the syn- symptoms, the long-term prognosis for excellent drome; others have come to a similar conclu- patients with Mollaret meningitis is excellent. sion. 7,11,13,19 There have been numerous It is important that physicians be aware of this reports of antibody confirmation, tissue cul- disorder because once it is identified, the ture growth, or positive polymerase chain patient may be spared multiple hospitaliza- reaction for herpes simplex virus in patients tions, extensive diagnostic evaluations, and with Mollaret meningitis.16-12,19-24 Current unnecessary treatments. Ea opinion supports herpes simplex virus as the likely cause. m REFERENCES Observations of increased peripheral 1. Mollaret P. Meningitis endothelioleukocytaire multi-recur- eosinophil counts and elevated serum IgM rente benigne: syndrome nouveau ou maladie nouvelle? Rec Neurol 1944; 76:57-76. levels in several patients also suggest a pro- 2. Hermans PE, Goldstein NP, Wellman WE. Mollaret's posed allergic origin of this disorder. meningitis and differential diagnosis of recurrent menin- gitis: report of case, with review of the literature. Am J Med 1970; 52:128-140. • THERAPY 3. Chadarevian JP, Becker WJ. Mollaret's recurrent aseptic meningitis: relationship to epidermoid cysts. Light micro- What is the treatment for Mollaret menin- scopic and ultrastructural cytological studies of the cere- brospinal fluid. J Neuropath Exp Neurol 1980; 39:661-669. 2 gitis? 4. Coleman W, Lischner H, Graver W. Recurrent aseptic meningitis without sequelae. J Ped 1975; 87:89-91. • Antibiotics 5. Goldi AP. Benign recurrent aseptic meningitis (Mollaret's meningitis): Case report and clinical review. Arch Neurol • Antihistamines 1979; 36:657-658. • Corticosteroids 6. Haynes BF, Wright R, McCracken JP. Mollaret's meningitis.

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 3 MARCH 2001 205 Downloaded from www.ccjm.org on October 9, 2021. For personal use only. All other uses require permission. CHANG AND COLLEAGUES Dear Doctor:

A report of three cases. JAMA 1976; 236:1967-1969. As editors, we'd like you 7. Jensenius M. Myrvang B, Storvold G, Bucher A, Helium KB, Bruu AL. Herpes simplex virus type 2 DNA detected in to look into every issue, cerebrospinal fluid of 9 patients with Mollaret's meningi- tis. Acta Neurol Scan 1998; 98:209-212. every page of the 8. Mascia RA, Smith CW. Mollaret's meningitis: an unusual disease with a characteristic presentation. Am J Med Sci Cleveland Clinic Journal 1984; 287:52-53. 9. Monteyne P, Sindic CJM, Laterre EC. Recurrent meningitis of Medicine. and associated with Herpes simplex type 2: demonstration by polymerase chain reaction. Eur Neurol 1996; 36:176-177. We'd like to know... 10. Steel JG, Dix RD, Baringer JR. Isolation of herpes simplex virus type 1 in recurrent (Mollaret) meningitis. Ann Neurol 1981; 11:17-21. 1 How many issues do you look into? 11. Teddar DG, Ashley R, Tyler KL, Levin MJ. Herpes simplex virus infection as a cause of benign recurrent lymphocytic Here's our goal: meningitis. Ann Intern Med 1994; 121:334-338. E'AII DMost DHalf DFew 12. Wolontis S, Jeannson S. Herpes type 2 meningitis follow- ing herpes progenitalis. West J Med 1975; 123:490-491. 13. Yamamoto U, Tedder DG, Ashley R, Levin MJ. Herpes sim- 2 How do you read the average issue? plex virus type 1 DNA in cerebrospinal fluid of a patient with Mollaret's meningitis. N Engl J Med 1991; Here's our goal: 325:1082-1085. 14. Bryun GW, Straathof J, Raymakers G. Mollaret's meningi- Etover-to-cover tis: differential diagnosis and diagnostic pitfalls. • Most articles 1962; 12:745-753. • Selected articles 15. Cantu RC, Wright RL. Aseptic meningitic syndrome with cauda equina epidermoid tumor. J Pediatr 1968; 73:114-116. 16. Schwartz JF, Balentine JD. Recurrent meningitis due to an intracranial epidermoid. Neurology 1978; 28:124-129. We put it in writing... 17. Mollaret P. Benign recurrent pleocytic meningitis and its please put it in writing for us. presumed causative virus. J Nerv Ment Dis 1952; We want to hear from you. 116:1072-1080. 18. Nordbring F, Gertzen O. Case report: benign recurrent aseptic meningitis (Mollaret's meningitis). Scan J Infect CLEVELAND CLINIC JOURNAL OF MEDICINE Dis 1971; 3:75-78. 19. Gignoux L, Ryvlin P, Najioullah F, Mauguiere F. Meningite The Cleveland Clinic Foundation multirecurrente de Mollaret d'origine herpetique. 9500 Euclid Avenue, NA32 [Recurrent Mollaret meningitis of herpetic origin.) Presse Cleveland, Ohio 44195 Med 1998; 27:1470-1472. 20. livanainen M. Benign recurrent aseptic meningitis of unknown etiology. Acta Neurol Scand 1973; 40:265-276. PHONE 216.444.2661 21. Stalder H, Oxman MN, Dawson DM. Herpes simplex FAX 216.444.9385 meningitis: isolation of herpes simplex virus type 2 from cerebrospinal fluid. N Engl J Med 1973; 289:1296-1298. E-MAIL [email protected] 22. Fodor PA, Levin MJ, Weinberg A, Sandberg E, Sylman J, Tyler KL. Atypical herpes simplex virus encephalitis diag- nosed by PCR amplification of viral DNA from CSF. Neurology 1998; 51:554-560. 23. Zunt JR, Marra CM. Cerebrospinal fluid testing for the diagnosis of infection. Neurol Clin 1999; 17(4):675-689. 24. Pruitt A. Infections of the nervous system. Neurol Clin 1998; 16:419-448.

ADDRESS: Natalie G. Correia, Department of General Internal Medicine, E13, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected].

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