Postgrad Med J: first published as 10.1136/pgmj.54.636.682 on 1 October 1978. Downloaded from Postgraduate Medical Journal (October 1978) 54, 682-685

A case of Mollaret's associated with a lymphoma I. M. SWITHINBANK M. 0. RAKE B.A., M.B., B.Chir., M.R.C.P. B.Sc., M.B., M.R.C.P.

Kent and Canterbury Hospital, Canterbury CTJ 3NG

Summary by a feeling of general malaise with development of A patient with recurrent benign meningitis (Mollaret's (39-40'C) and sweating. During the ensuing meningitis) responding to treatment with colchicine 24-30 hr, gradually increased with photo- by a reduction in frequency of attacks who has phobia in severe attacks. Confusion and disorient- subsequently developed a non-Hodgkin's lymphoma is ation also occurred and meningism developed. described. Over the next 4-5 days the symptoms subsided, the patient returned to normal and remained perfectly Introduction well until the next attack. Recurrent attacks of benign meningitis, first Examination both during and between attacks described by Mollaret (1945) are rare. Since then, a showed no abnormality apart from the severe number of case reports have appeared (George and meningism during an attack which disappeared Westphal, 1965; livanainan, 1973; Nordbring and within 3-4 days. Investigations showed that during Gertzein, 1971). Reviews by Hermans, Goldstein attacks there was a rise in peripheral WBC Protected by copyright. to and Wellman (1972) and Bruyn, Straathof and 15 0 x 109/1 with 88%Y. polymorphs, 1 Y lymphocytes Raymakers (1962) list twenty well documented and 1% monocytes. No rise in eosinophil count was cases in the world literature. noted. A rise in ESR to 47 mm in the first hour also Mollaret's meningitis consists of intermittent occurred. No abnormalities were detected in liver or attacks of acute meningitis. Symptoms of general renal function. examination was ill-health and diffuse myalgia progress to develop- performed and has been repeated both during and ment of a fever (up to 39°C) and in between attacks (Table 1). of acute meningitis. There may be some depression Culture of CSF, blood, urine, sputum, faeces, of conscious level, but focal neurological signs are bone marrow and lymph node showed no growth of rare. An attack lasts about 5 days. Recovery is bacteria, fungi or viruses. Leptospira complement complete with no neurological sequelae. CSF cell fixation test and Toxoplasma dye test were negative. count shows an increase in polymorphs, lymphocytes Serology for fungal and viral antibodies showed no and large, fragile, mononuclear cells (endothelial rises in titre. cells). CSF protein is raised, glucose is normal. X-rays of skull, sinuses and lumbar spine showed http://pmj.bmj.com/ All attempts to culture a pathogen have been in vain. no abnormalities. scan and RISA* cisterno- The CSF returns to normal in parallel with the gram were normal. Air encephalogram showed clinical syndrome. moderate dilatation of the lateral ventricles, other- wise no abnormality. EEG (not during an attack) Case history showed a diffuse, mainly posterior, bitemporal A 63-year-old male retired office worker presented dysrhythmia of minor nature. Bone marrow biopsy in January 1973 with a 1-year history of recurrent was normal. bouts of fever, sweating and severe . Serum was negative for auto-antibodies and anti- on September 29, 2021 by guest. There had been seven attacks at irregular intervals nuclear factor. DNA binding was less than 5%. of between 1 and 3 months. Heaf test was positive. Kveim test was negative. Apart from a short febrile illness whilst in Dunedin, There was no excess of urinary VMA or 5-HIAA. New Zealand, in February 1971 as part of a world The patient's immunological competence was tour, there was no other relevant medical or family investigated and found to be normal, except for a history. slightly raised IgG and a very high serum IgE level. The attacks started with a diffuse erythematous- CSF immunoglobulins were within normal limits urticarial rash mainly on the trunk and legs followed between and during attacks. During an attack C3 was elevated to 1-95 0 5- There Requests for offprints: Dr M. 0. Rake, B.Sc., M.B., g/l (normal 1-6). M.R.C.P., Consultant Physician, Kent and Canterbury was no excess conversion of complement or complex Hospital, Canterbury, Kent, CTI 3NG. * Radio-active iodinated serum albumin. 0032-5473/78/1000-0682 $02.00 (© 1978 The Fellowship of Postgraduate Medicine Postgrad Med J: first published as 10.1136/pgmj.54.636.682 on 1 October 1978. Downloaded from Case reports 683

TABLE 1. CSF results Protein RBC WBC Polymorphs Lymphocytes Date g/l x 1012/1 x 109/1 % During attacks 20 March 73 1-65 - 2140 99 1 10 May 73 2-50 - 1400 95 5 Between attacks, e.g. 4 Sept 93 0-20 - - - - During attacks 9 Oct 73 0-80 20 350 95 5 May 1974 0 85 1550 2100 100 - 28 June 74 1-86 - 240 70) remainder of > each appeared 10 July 74 0-76 - 670 759 degenerate 29 July 74 1-86 - 700 100 During attacks whilst on colchicine 20 Jan 75 0-54 44 92 10 90 23 June 75 0-38 204 390 95 5 During attacks 10 Jan 76 0 85 - 200 100

Pyrimethonine Protected by copyright. PrednisoloneL¶L~~~~~ LEII~Coichicine ~...... Colchicine

1972 1973 1974 1975 1976 1977 FIG. 1. Diagram showing individual attacks of meningitis related to treatment. IZ 71 75 1W 1 http://pmj.bmj.com/ initiated activity. Nitro-blue tetrazolium (NBT) no hepatosplenomegaly. Repeat biopsy of a supra- testing, performed on blood and CSF between and clavicular node showed histology similar to before, during attacks, showed no abnormality. but appeared more likely to be lymphomatous on this Attacks continued during 1973/74 unaltered by occasion (Fig. 2). treatment (Table 1). Chest X-ray and hilar tomography showed right On 8th January 1975 a trial of colchicine was hilar gland enlargement. Intravenous urogram was

started at a dose of 0-5 mg twice/day, later increasing normal. Bilateral pedal lymphangiogram showed on September 29, 2021 by guest. to 0 5 mg thrice/day. There was a dramatic reduction pathologically enlarged lymph nodes in the left in- in the frequency of attacks (Fig. 1). guinal and left iliac areas. There were probable In July 1975 an enlarged left supraclavicular abnormal nodes in the right iliac area. The para- lymph node was palpated. In January 1976 enlarged aortic nodes were equivocal. 99Tc sulphur colloid axillary and inguinal nodes were also demonstrated. liver/spleen scan showed a normal liver outline with a A biopsy of the supraclavicular node showed low overall count-rate suggestive of diffuse liver excessive lymphocytic proliferation and fibrosis not disease. Bone marrow (iliac spine biopsy) (Fig. 3) diagnostic of or neoplasia. No treat- showed heavy diffuse infiltration with lymphocytes ment was given and the lymphadenopathy had and lymphoblasts. There was a pronounced fine almost completely subsided by June 1976. reticulin network. Sternberg-Reed cells were not By January 1977 glands were again palpable in the seen; there was no excess of plasma cells. The picture left supraclavicular fossa, axilla and groin. There was was that of a non-Hodgkin's lymphoma (Stage IVa). Postgrad Med J: first published as 10.1136/pgmj.54.636.682 on 1 October 1978. Downloaded from 684 Case reports

carial skin rash has been reported in one previous %~~~~~~~~~~~~~~~~~~~o case of Mollaret's meningitis (George and Westphal, 1965). This case also showed other systemic symp- toms and the authors commented that she re- presented a combination of the features of familial Mediterranean fever (FMF) and Mollaret's rO $~t~~ meningitis. Attacks of Mollaret's meningitis are unpredictable. Many cases have been reported in which attacks spontaneously ceased after many years. This makes assessment of a treatment of one patient difficult. A trial of colchicine was started (Gledhill et al., 1975) following reports of its success in reducing the frequency of attacks of FMF (Zemer et al., 1974; Dinarello et al., 1974). The mode of action is unknown. Colchicine is a spindle poison - inhibiting FIG. 2. Biopsy of the supraclavicular node, January 1977 mitosis at metaphase (Inone, 1959). It has also been x 245, shows diffuse lymphocytic proliferation. shown to interfere with polymorph function in vitro (Malawista and Bodel, 1967; Rajan, 1966). This could explain the inhibition of recurrent attacks of inflammation in FMF and Mollaret's meningitis. *D4~~~r~~a t.. ji%T-J% During colchicine therapy the patient developed a non-Hodgkin's lymphoma. The pathogenesis of Protected by copyright. to this is uncertain: it may be co-incidental, or it may be related to colchicine therapy. Although colchicine is known to produce chromosomal abnormalities (Ferreira, Buoniconti and Frota-Pessoa, 1973), the development of malignant disease in patients on 0.rr0 long-term colchicine has not been described. The development of a lymphoma may be a complication of Mollaret's meningitis-possibly analogous to amyloid in FMF. Alternatively, if the lymphoma is regarded as the primary condition, then the meningitis may be a secondary phenomenon. This is similar to the recurrent fever which is a well described (but rare) feature of Hodgkin's disease and other lymphomas (Reimann, 1977). FIG. 3. Marrow biopsy (iliac spine) x 245, showing Mollaret's meningitis remains a disease whose http://pmj.bmj.com/ diffuse infiltration by lymphocytes and lymphoblasts. cause is unknown. It does not appear to be inherited. There are similarities and overlapping of symptoms with FMF. Both respond to colchicine prophylaxis. Discussion The occurrence of recurrent febrile episodes is a This case demonstrates the essential features of common factor between Mollaret's meningitis, Mollaret's meningitis - recurrent meningitis, with FMF and some lymphomas. All are diseases of

complete recovery between attacks. Apart from unknown pathogenesis which may be linked by on September 29, 2021 by guest. confusion during attacks, there were no neurological some abnormality of the immunological system. signs. Involvement of other organ systems was confined to the occurrence of a skin rash during most attacks. Attacks occurred irregularly and continued References with considerable frequency for three years until BRUYN, G.W., STRAATHOF, L.J.A. & RAYMAKERS, G.M.J. colchicine was started. The frequency of attack was (1962) Mollaret's meningitis. Differential diagnosis and diagnostic pitfalls. . Minneapolis, 12, 745. reduced, increasing again on stopping colchicine DINARELLO, C., WOLFF, S., GOLDFINGER, S.E., DALE, D.C. & temporarily (the disease was complicated by the ALLING, D.W. (1974) Colchicine therapy for FMF: a development of a non-Hodgkin's lymphoma). double blind trial. New England Journal of Medicine, 291, The signs and symptoms of Mollaret's meningitis 934. FERREIRA, N.R., BUONICONTI, A. & FROTA-PESSOA, 0. (1973) are usually confined to the Colchicine therapy and aneuploid cells. Revista Brasileira (Hermans et al., 1972). The occurrence of an urti- de Pesquisas Medicas e Biologicas, 6, 141. Postgrad Med J: first published as 10.1136/pgmj.54.636.682 on 1 October 1978. Downloaded from Case reports 685

GEORGE, R.B., WESTPHAL, R.E. (1965) Periodic meningitis. sumption in human leucocytes. Journal of Clinical Investi- An unusual manifestation of periodic disease. Annals of gation, 46, 786. Internal Medicine, 62, 778. MOLLARET, M. (1945) La meningite endothelio-leucocytaire GLEDHILL, R.F., LEWIS, P.D., MARSDEN, C.D. & RAKE, M.O. multirecurrente b6nigne, syndrome nouveau ou maladie (1975) Is Mollaret's meningitis another periodic disorder nouvelle? Annales de l'Institut Pasteur de Lille, 71, 1. responsive to colchicine? Lancet, ii, 415. NORDBRING, F. & GERTZEIN, O., (1971) Benign recurrent HERMANS, P.E., GOLDSTEIN, N.P. & WELLMAN, W.E. (1972) aseptic meningitis (Mollaret's meningitis). Scandinavian Mollaret's meningitis and differential diagnosis of re- Journal of Infectious Diseases, 31, 75. current meningitis. American Journal of Medicine, 52, 128. IIVANAINAN, M. (1973) Benign recurrent aseptic meningitis RAJAN, K.T. (1966) Lysosomes and gout. Nature. London, of unknown aetiology (Mollaret's meningitis). Acta 210, 959. neurologica scandinavica, 49, 133. REIMANN, H.A. (1977) Periodic (Pel-Ebstein) fever of lym- INONE, S. (1959) The effect of colchicine on the microscopic phomas. Annals of Clinical and Laboratory Science, 7, 1. and submicroscopic structure of the mitotic spindle. ZEMER, D., REVACH, M., PRAS, M., MODAN, B., SCHOR, S., Experimental Cell Research (Suppl. 1), 450. SOHAR, E. & GAFRI, J. (1974) A controlled trial ofcolchicine MALAWISTA, S.E. & BODEL, P.T. (1967) The dissociation by in preventing attacks of FMF. New England Journal of colchicine of phagocytosis from increased oxygen con- Medicine, 291, 932. Protected by copyright. http://pmj.bmj.com/ on September 29, 2021 by guest.