IM BOARD REVIEW DAVID L LONGWORTH, MD, JAMES K. STOLLER, MD, EDITORS

DAVID Z. CHANG, MD, PHD Department of Internal Medicine, Cleveland Clinic

NATALIE G. CORREIA, DO Department of General Internal Medicine, Cleveland Clinic

PARVINDER KHURANA, M D Department of Internal Medicine, Cleveland Clinic

RALPH J. TUTHILL, M D Department of Anatomic Pathology, Cleveland Clinic

ALAN J. TAEGE, M D Department of Infectious Disease, Cleveland Clinic

A SELF-TEST ON A CLINICAL CASE

A 35-year'old man with recurrent aseptic meningitis

35-YEAR-OLD, previously healthy white man presented to the emergency

department because of severe headache, nau-sea, vomiting, photophobia, neck stiffness, and fever (temperature 104°F—40°C), which had begun 1 day previously. He stated that he had not experienced visual changes, rash, or trauma. In addition, he had not recently trav-eled or come into contact with anyone known to have tuberculosis, and he had no known risk factors for human immunodeficiency virus.

The patient had experienced two similar episodes during :he preceding 12 months. He was treated both times with a brief course of intravenous antibiotics pending cerebrospinal fluid cultures and thereafter for symptom relief. After each episode, he recovered with-out residual neurologic deficits or other seque-lae. Routine bacterial cultures of the cere-brospinal fluid and a culture for enterovirus were performed, but no specific cause was ever found.

• PHYSICAL EXAMINATION

The patient has the room darkened, saying he has a headache and cannot stand the light. His vital signs are: • Temperature 37.8°C (100.0T) • Pulse 64 • Blood pressure 131/58 mm Hg.

On examination, the patient has nuchal rigidity, and any movement of his neck wors-ens the pain. There are no cranial nerve deficits. The motor and sensory examinations are unremarkable. Deep tendon reflexes are 2+ and symmetric without evidence of the Babinski sign. The Kernig and Brudzinski signs are not present. There are no petechial

or purpuric lesions. The chest, heart, lungs, and abdomen are within normal limits.

Diagnostic tests Cerebrospinal fluid analysis. A lumbar

puncture was performed in the emergency room. The cerebrospinal fluid was turbid with the following values: • Red blood cells 68/pL (normal 0 - 1 ) • White blood cells 385/juL (normal 0-3) ; lymphocytes 68%, monocytes 27%, neu-trophils 1% • Gram stain: no organisms found • Protein 164 mg/dL (normal 20-50) • Glucose 45 mg/dL (normal 50-75) • Tests for infective organisms: all negative, including the following: herpes simplex virus type 1 and type 2 DNA polymerase chain reaction, cryptococcal antigen, fungal serolo-gy, Lyme disease serology, culture for acid-fast bacilli, rapid plasma reagin test for syphilis, and HIV screening.

Magnetic resonance imaging of the brain with and without gadolinium contrast was consistent with acute and chronic sinusitis but was otherwise negative.

Another spontaneous resolut ion The patient was initially treated with a course of intravenous ceftriaxone pending cere-brospinal fluid culture results. The antibiotics were discontinued on the fourth hospital day when the results showed only Staphylococcus epidermidis, which was thought to be a conta-minant on the basis of the clinical picture. The persistent headache was treated symptomati-cally. The nuchal rigidity gradually resolved and the patient was subsequently discharged. During a follow-up evaluation, there was no evidence of neurologic sequelae.

Tests for infectious organisms were negative

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Although Behcet syndrome and coidosis are associated with aseptic meningi-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 infections 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 viral meningitis 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.

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• 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

FIGURE 1. T h i n P r e p sl ides o f t h e p a t i e n t ' s c e r e b r o s p i n a l f l u i d . Top, n u m e r o u s m o n o c y t o i d M o l l a r e t cells w i t h d e l i -ca te a t t e n u a t e d c y t o p l a s m a re p r e s e n t . P a p a n i c o l a o u s ta in , x 200 . B o t t o m , M o l l a r e t cells have i r r e g u l a r l y s h a p e d nuc le i . T h e n u c l e a r d i a m e t e r is o f t e n n a r r o w a t o n e e n d a n d w i d e a t t h e o p p o s i t e e n d . P a p a n i c o l a o u s ta in , x 400 .

DIFFERENTIAL DIAGNOSIS

1 • • • • •

What is the most likely cause of this patient's symptoms?

Aseptic viral meningitis Fungal infection Mollaret meningitis Sarcoidosis Behcet syndrome

The differential diagnosis includes causes of culture-negative meningitis.

Signs and symptoms Sudden onset of meningeal signs and symp-toms and rapid resolution without neurologic sequelae characterize Mollaret meningitis. Patients present with recurrent attacks of meningismus that are sudden in onset and last from 1 to 7 days. Fever is generally present, although severa. patients were afebrile in reported cases.4

Malaise, arthralgia, myalgia, nausea, and vomiting are common. Approximately 50% of patients have transient signs and symptoms related to the attack on the central nervous system.8 These include seizures, hallucina-tions, coma, vertigo, syncope, speech abnor-malities, anisocoria, seventh nerve paresis, decreased deep tendon reflexes, Babinski sign, and paresis. All signs and symptoms disappear within 24 to 96 hours, and the patient feels entirely well until the next episode. The dis-ease never leaves any residual neurologic or systemic signs or symptoms.

The attacks occur irregularly, and the

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symptom-free intervals last from weeks to years. It is not possible to predict which attack will be the last: the disorder generally persists for 3 to 5 years but has been reported to per-sist as long as 20 years, during which the patient may experience 30 or more separate attacks of aseptic meningitis.

C e r e b r o s p i n a l f lu id f e a t u r e s During attacks, the cerebrospinal fluid is under increased pressure and has an elevated white blood cell count, increased protein con-tent, and a glucose level usually in the low-to-normal range with occasional hypoglycor-rhachia.

Mollaret cells. The most distinctive fea-ture of the cerebrospinal fluid is the presence of numerous large monocytoid cells called Mollaret cells. These have a prominent cyto-plasm and large irregular nuclei (F I G U R E 1 ) . The cytoplasm is delicate and easily distorted when placed on a slide for microscopy. The nuclei are characteristically broad at one end and narrow at the opposite end. (On air-dried preparations, the broad end may exhibit toe-like projections. This latter change is not seen on fluid ThinPrep slides.) Mollaret cells read-ily degenerate and disappear from the cere-brospinal fluid and are rarely seen 18 to 24 hours after the onset of an attack, most likely because the cytoplasm is so delicate.

Mollaret initially considered the cells to be derived from endothelium and called them "endothelial leukocytes." However, they are now considered to be blood-derived mono-cytes. If the diagnosis is suspected, cere-brospinal fluid cytology should be ordered and the reviewing pathologist should be informed.

Diagnos is The diagnosis of Mollaret meningitis requires exclusion of other conditions that may have similar clinical presentations (T A B L E 1 ) .

In our patient, the diagnosis of Mollaret meningitis was based on several factors: • The characteristic clinical presentation

was consistent with viral meningitis • No pathogen could be identified • There was no evidence to support the

diagnosis of other conditions that might produce a similar clinical picture

• Examination of the cerebrospinal fluid

T A B L E 1

D i f f e r e n t i a l d i a g n o s i s o f M o l l a r e t m e n i n g i t i s

Infections Idiopathic recurrent bacterial meningit is Brain, spinal, or cranial epidural abscess Viral meningit is Cryptococcosis and other fungal infections Brucellosis Leptospirosis Tuberculosis Cerebral hydatid cyst

Defective immune mechanisms Hypoimmunoglobul inemia Sickle cell anemia Chronic lymphocytic leukemia Mult ip le myeloma Lymphocytic lymphosarcoma Lupus erythematosus Splenectomy

Intracranial and intraspinal tumors Cerebral hemangioma Ependymoma Craniopharyngioma Glioblastoma Intraspinal tumors Intracranial epidermoid tumor

Congenital conditions Myelomeningocele Midl ine cranial or spinal dermal sinus Petrous fistula Neurenteric cysts

Other Sarcoidosis Behcet syndrome Vogt-Koyanagi syndrome Harada syndrome Familial Mediterranean fever Whipple disease

ADAPTED FROM HERMANS PE, GOLDSTEIN NP, WELLMAN WE. MOLLARET'S MENINGITIS AND DIFFERENTIAL DIAGNOSIS OF

RECURRENT MENINGITIS: REPORT OF CASE, WITH REVIEW OF THE LITERATURE. AM J MED 1970; 52:128-140.

revealed Mollaret cells Bryun et al14 established the following

diagnostic criteria for Mollaret meningitis: • Recurrent attacks of fever associated with

signs and symptoms of meningeal irrita-tion

In Mollaret meningitis, symptom-free intervals last weeks to years

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• Attacks separated by symptom-free inter-vals lasting for weeks to months

• Cerebrospinal fluid pleocytosis of mixed type including endothelial cells, leuko-cytes, and lymphocytes during attacks

• Periods of remission without residual signs • No causative organism detectable.

Goldi5 suggested the following amend-ments to Bryun's original criteria: • Fever may be absent • Approximately 50% of patients have tran-

sient neurologic symptoms or signs in addition to meningeal irritation

• The symptom-free intervals may vary from a few days to years

• There may be increased gamma globulin fraction in the cerebrospinal fluid.

Possible causes of Mo l l a re t meningit is Mollaret meningitis has generally been con-sidered a disease of unknown cause. In some reports, epidermoid tumors leaked contents that were capable of inducing an inflammato-ry response, suggesting that this might be a cause of Mollaret meningitis.3-15-16 Viral cau-sation has also been considered since the orig-inal characterization of Mollaret meningitis. Mollaret himself isolated an "ultravirus" in a case he reported.1?

Nordbring and Gertzen18 postulated that herpes simplex virus is a cause of the syn-drome; others have come to a similar conclu-sion. 7 ,11 ,13 ,19 There have been numerous reports of antibody confirmation, tissue cul-ture growth, or positive polymerase chain reaction for herpes simplex virus in patients with Mollaret meningitis.16-12,19-24 Current opinion supports herpes simplex virus as the likely cause.

Observations of increased peripheral eosinophil counts and elevated serum IgM levels in several patients also suggest a pro-posed allergic origin of this disorder.

• THERAPY

2 What is the treatment for Mollaret menin-gitis?

• Antibiotics • Antihistamines • Corticosteroids

• Colchicine • Treatment of symptoms • None of the above

There is no specific therapy for this disease. Various antibiotics and antihistamines have been tried but did not alter the natural course of the disorder. Colchicine has been tried because of the similarity between Mollaret meningitis and familial Mediterranean fever and because it has been reported to decrease the severity and frequency of attacks.

More recently, it has been suggested that patients with frequent attacks may benefit from prophylactic acyclovir, which is effective in preventing clinically apparent recurrent bouts of herpes simplex virus infection.13 In one reported case the number of episodes decreased after corticosteroid treatment."1

We started our patient on acyclovir 400 mg twice daily. He has been followed by the infectious disease clinic for 18 months, and has been doing well without further episodes of meningitis at the time of this writing. We plan to continue acyclovir for 2 years, though this plan is not based on specific data.

• PROGNOSIS

Although acute episodes can cause disabling symptoms, the long-term prognosis for patients with Mollaret meningitis is excellent. It is important that physicians be aware of this disorder because once it is identified, the patient may be spared multiple hospitaliza-tions, extensive diagnostic evaluations, and unnecessary treatments. Ea

m REFERENCES 1. M o l l a r e t P. Meningitis endothelioleukocytaire multi-recur-

rente benigne: syndrome nouveau ou maladie nouvelle? Rec N e u r o l 1944; 7 6 : 5 7 - 7 6 .

2. H e r m a n s PE, G o l d s t e i n NP, W e l l m a n W E . Mo l la re t ' s men ing i t is a n d d i f f e r e n t i a l d iagnosis o f recur ren t m e n i n -gitis: r e p o r t o f case, w i t h r e v i e w of t h e l i t e ra ture . A m J M e d 1970; 5 2 : 1 2 8 - 1 4 0 .

3. C h a d a r e v i a n JP, Becker WJ. Mo l la re t ' s recur ren t asept ic meningi t is : re la t ionship t o e p i d e r m o i d cysts. L ight micro-scopic a n d u l t rast ructura l cyto logical studies o f t h e cere-brospinal f lu id . J N e u r o p a t h Exp N e u r o l 1980; 3 9 : 6 6 1 - 6 6 9 .

4. C o l e m a n W , Lischner H, G r a v e r W . Recur rent asept ic men ing i t i s w i t h o u t seque lae . J Ped 1975; 8 7 : 8 9 - 9 1 .

5. Gold i AP. Ben ign recur rent aseptic m e n i n g i t i s (Mo l la re t ' s meningi t is ) : Case r e p o r t a n d clinical rev iew. Arch Neuro l 1979; 3 6 : 6 5 7 - 6 5 8 .

6. H a y n e s BF, W r i g h t R, M c C r a c k e n JP. M o l l a r e t ' s mening i t is .

Long-term prognosis: excellent

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A r e p o r t o f t h r e e cases. J A M A 1976; 2 3 6 : 1 9 6 7 - 1 9 6 9 . 7. Jensenius M . M y r v a n g B, S t o r v o l d G, Bucher A , H e l i u m

KB, Bruu AL . Herpes s implex virus t y p e 2 D N A d e t e c t e d in cerebrosp ina l f l u id o f 9 pa t ien ts w i t h M o l l a r e t ' s m e n i n g i -tis. A c t a N e u r o l Scan 1998; 9 8 : 2 0 9 - 2 1 2 .

8. Mascia RA, S m i t h C W . Mo l la re t ' s men ing i t i s : a n unusua l disease w i t h a character ist ic p r e s e n t a t i o n . A m J M e d Sci 1984; 2 8 7 : 5 2 - 5 3 .

9. M o n t e y n e P, Sindic CJM, Later re EC. R e c u r r e n t m e n i n g i t i s a n d encephal i t is associated w i t h Herpes s implex t y p e 2: d e m o n s t r a t i o n by p o l y m e r a s e cha in reac t ion . Eur N e u r o l 1996; 3 6 : 1 7 6 - 1 7 7 .

10. Steel JG, D ix RD, Bar inger JR. Isolat ion o f h e r p e s s implex virus t y p e 1 in recur ren t ( M o l l a r e t ) m e n i n g i t i s . A n n N e u r o l 1981 ; 1 1 : 1 7 - 2 1 .

11. Teddar DG, A s h l e y R, Tyler KL, Levin MJ. H e r p e s s implex virus in fec t ion as a cause of b e n i g n r e c u r r e n t l ymphocyt ic mening i t is . A n n In te rn M e d 1994; 1 2 1 : 3 3 4 - 3 3 8 .

12. W o l o n t i s S, J e a n n s o n S. Herpes t y p e 2 m e n i n g i t i s f o l l o w -ing herpes progeni ta l is . W e s t J M e d 1975; 1 2 3 : 4 9 0 - 4 9 1 .

13. Y a m a m o t o U , T e d d e r DG, A s h l e y R, Levin M J . Herpes sim-plex virus t y p e 1 D N A in cerebrosp ina l f l u i d o f a p a t i e n t w i t h Mo l la re t ' s mening i t is . N Engl J M e d 1991; 3 2 5 : 1 0 8 2 - 1 0 8 5 .

14. Bryun G W , S t r a a t h o f J, R a y m a k e r s G. M o l l a r e t ' s m e n i n g i -tis: d i f f e r e n t i a l d iagnosis a n d d iagnost ic pi t fa l ls . N e u r o l o g y 1962; 1 2 : 7 4 5 - 7 5 3 .

15. Can tu RC, W r i g h t RL. Asept ic m e n i n g i t i c s y n d r o m e w i t h cauda e q u i n a e p i d e r m o i d t u m o r . J Pediat r 1 9 6 8 ; 7 3 : 1 1 4 - 1 1 6 .

16. S c h w a r t z JF, B a l e n t i n e JD. Recur rent m e n i n g i t i s d u e t o a n in t racrania l e p i d e r m o i d . N e u r o l o g y 1978; 2 8 : 1 2 4 - 1 2 9 .

17. M o l l a r e t P. Ben ign recur ren t pleocyt ic m e n i n g i t i s a n d its p r e s u m e d causat ive virus. J Nerv M e n t Dis 1 9 5 2 ; 1 1 6 : 1 0 7 2 - 1 0 8 0 .

18. N o r d b r i n g F, G e r t z e n O. Case repor t : b e n i g n r e c u r r e n t aseptic men ing i t i s ( M o l l a r e t ' s men ing i t is ) . Scan J In fect Dis 1971 ; 3 : 7 5 - 7 8 .

19. G i g n o u x L, Ryvl in P, N a j i o u l l a h F, M a u g u i e r e F. Meningite multirecurrente de Mollaret d'origine herpetique. [Recurrent M o l l a r e t men ing i t i s o f he rpe t ic o r i g i n . ) Presse M e d 1998; 2 7 : 1 4 7 0 - 1 4 7 2 .

20. l i v a n a i n e n M . Ben ign recur ren t aseptic m e n i n g i t i s o f u n k n o w n e t io logy . Acta N e u r o l Scand 1973; 4 0 : 2 6 5 - 2 7 6 .

21. S ta lder H, O x m a n M N , D a w s o n D M . Herpes s imp lex meningi t is : isolat ion o f herpes s implex virus t y p e 2 f r o m cerebrospina l f lu id . N Engl J M e d 1973; 2 8 9 : 1 2 9 6 - 1 2 9 8 .

22. Fodor PA, Levin MJ, W e i n b e r g A , S a n d b e r g E, S y l m a n J, Tyler KL. Atyp ica l herpes s implex virus e n c e p h a l i t i s d i a g -nosed by PCR a m p l i f i c a t i o n o f v ira l D N A f r o m CSF. N e u r o l o g y 1998; 5 1 : 5 5 4 - 5 6 0 .

23 . Z u n t JR, M a r r a C M . Cerebrosp ina l f lu id t e s t i n g f o r t h e diagnosis o f cent ra l nervous system i n f e c t i o n . N e u r o l Clin 1999; 1 7 ( 4 ) : 6 7 5 - 6 8 9 .

24 . Prui t t A . In fect ions o f t h e nervous system. N e u r o l Clin 1998; 1 6 : 4 1 9 - 4 4 8 .

ADDRESS: Natalie G. Correia, Department of General Internal Medicine, E13, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail correin@ccf.org.

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