Journal ofNeurology, Neurosurgery, and Psychiatry 1991;54:275-276 275 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.3.275 on 1 March 1991. Downloaded from SHORT REPORT

Aseptic associated with high dose intravenous

J D G Watson, J Gibson, D E Joshua, H Kronenberg

Abstract frontal headache and on day four rigors, Two cases of aseptic meningitis occurred sweating, nausea, myalgia, photophobia and in temporal association with high dose neck stiffness were reported. Her temperature intravenous immunoglobulin therapy to was 37-5°C, Kernig's sign was absent and treat thrombocytopenia. In neither case there were no focal neurological signs. was any other aetiological agent The next day a non-contrast CT scan of the identified and both patients completely was normal and a recovered within a few days. This demonstrated clear (CSF) phenomenon has been reported in only with a pressure of 230 mm H20. The CSF cell one previous paediatric case. count was 2 x 106/1 red cells and 22 x 106/1 white cells. The white cell differential was High dose intravenous immunoglobulin 64% lymphocytes, 3% monocytes and 33% (IVIg) therapy has been used with increasing neutrophils. The CSF protein was 0-48 g/l frequency for a range of indications, notably (normal 0-15-0-45) and the glucose 2-9 mM immune thrombocytopenic purpura (ITP).' (blood glucose 5-2 mM). A gram stain and a Side effects include fever, vomiting, transient direct examination for Cryptococci were headache and serum sickness like reactions.23 negative as was a CSF cryptoccal antigen test. Two adult patients with thrombocytopenia Blood cultures and subsequent serum viral developed transient aseptic meningitis in titres were negative. association with a course of high dose IVIg The patient was treated with analgesics but therapy. no . A repeat lumbar puncture on day nine revealed clear fluid with a pressure of Case 1 210 mm H20. Red and white cell counts were The first patient was a 25 year old female each 1 x 106/1, protein was 0 44 g/l and the university student who was diagnosed in glucose was 2-2 mM (blood glucose 4-1 mM).

Yugoslavia as having ITP at the age of 22. At The neurological symptoms slowly resolved http://jnnp.bmj.com/ that time her platelet count was 14 x 109/l and over the next few days and on day 15, when there were plentiful megakaryocytes on bone the platelet count was 297 x 109/1, a splen- marrow examination. She was initially reluc- ectomy was successfully performed. There tant to accept treatment but in 1988 (aged 24) were no post-operative complications and the was treated unsuccessfully with both pred- patient remained neurologically normal. Two nisone (50 mg/d for five weeks) and intra- months later her platelet count was venous immunoglobulin (IVIg). No details of 438 x 109/1. on September 25, 2021 by guest. Protected copyright. the formulation and dose of the IVIg are 2 Royal Prince Alfred available. Case Hospital, Later in 1988 the patient came to Australia The second patient was a 26 year old male who Camperdown, and was re-evaluated. Her platelet count was was born in the Lebanon, and migrated to New South Wales, x marrow were Australia at the age of 10 years. From about Australia 14 109/l and the bone findings Department of again consistent with ITP. She was anti- that time he suffered multiple episodes of easy nuclear antibody negative and unresponsive to bruising, purpura and epistaxis and had bled J D G Watson another trial of prednisone (50 mg/d for 15 profusely from a head laceration sustained in a Department of days). Splenectomy was recommended and car accident. His platelet count was consis- Haematology J Gibson the patient was admitted to hospital in March tently low, ranging from 14 to 28 x 109/1. When D E Joshua 1989 for a pre-operative course of high dose first seen at our hospital in 1980 the platelet half H Kronenberg IVIg, which in view of her previous lack of life was 50-60 hours and bone marrow examin- was a 1 ation Correspondence to: response, started at dose of g/kg/d.5 showed numerous megakaryocytes. Dr Gibson, The IVIg preparation used was Intragam Records elsewhere revealed that his two male Haematology Department, Royal Prince Alfred (CSL, Australia) which is a low pH formula- siblings also had thrombocytopenia but a Hospital, tion prepared with ethylene glycol6 and was female sibling was normal. There was no Missenden Road, Camperdown, NSW, given over eight to 12 hours. Before treatment consanguinity. On at least one occasion the Australia 2050 the platelet count was 9 x 109/l and by day platelet count responded modestly to pred- Received 6 April 1990 three it had risen to 251 x 109/1. The treatment nisone but the exact diagnosis remained and in revised form 25 June 1990. was then stopped. Late on day three the obscure. Accepted 5 July 1990 patient developed a progressively worsening Nevertheless, when he was admitted in July 276 Watson, Gibson, Joshua, Kronenberg J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.3.275 on 1 March 1991. Downloaded from 1989 to have a scalp lesion removed, it was prodromal features, absence of a history of decided to try a five day course of IVIg. The recent contact with others suffering from viral platelet count on admission was 16 x 109/1 and illnesses, no relevant recent travel and no he was given 0-4 g/kg/d of Intragam. On day identifiable rise in serum viral titres (case 1). three of treatment he experienced frontal Given the strong temporal association of headaches, nausea and vomiting, and on the meningitis with the high dose IVIg infusions next day neck stiffness, photophobia and a and the rapid resolution with cessation of this temperature of 37 3°-38&0°C. The infusion was therapy, we feel that they were aetiologically ceased. There were no focal neurological signs related. and a CT head scan without contrast was With such small numbers of reported cases, normal. A lumbar puncture, carried out after a very few conclusions can be drawn regarding platelet transfusion, showed slightly turbid the importance ofdose and formulation and the fluid with a pressure of 230 mm H20. There possible mechanisms of the aseptic meningitis. were 83 x 106 red cells and 131 X 106 white cells In Kato's patient4 and case 2, a dose of 0 4 g/ per litre. The white cell differential count was kg/d was used whilst in case 1 we used two 72% polymorphs, 26% lymphocytes and 2% and a half times this dose. At least three monocytes. Protein was 0-56 g/l and glucose separate preparations of HDIg have now been 3-3 mM (blood glucose eight hours earlier was implicated in this phenomena. Aseptic menin- 7-4 mM). gitis associated with drug therapy has been No organisms were seen on Gram stain, or reported infrequently, although well documen- grown on culture. Direct examination and ted cases attributed to cotrimoxazole and antigen test for Cryptococci were negative as azathioprine have been described.78 was culture including cultures for Myco- In conclusion, although headache and fever bacteria. Viral studies were not carried out and are a well recognised side effects of high dose blood cultures were negative. Intravenous IVIg, aseptic meningitis has only been repor- ampicillin, 2 g four hourly, was prescribed ted in one previous patient, a paediatric case. empirically after the lumbar puncture, but With the increasing use of this therapy for a stopped after three days because of rapid range of disorders including an expanding symptomatic improvement and the negative number of neurological disorders,9 this bacteriological results. By day seven he was phenomenon may be of considerable clinical neurologically normal but the platelet count significance. was only 28 x 109/1. Surgery was postponed but subsequently performed under platelet cover We thank Professor J McLeod for helpful discussion and Drs M Halmagyi (case 1) and J Ell (case 2) for their assistance in the two months later. When last reviewed in management of these patients. Ms M Alfonzo provided expert November 1989 he was still thrombocytopenic secretarial assistance. but otherwise well.

1 Bussel JB, Pham LC. Intravenous treatment with gamma- Discussion globulin in adults with immune thrombocytopenic The complications of high dose IVIg include a purpura: review of the literature. Vox Sang 1987;52: 206-11.

number of neurological symptoms such as 2 Matsumoto S, Kobayashi N, Gohya N. Clinical trials of http://jnnp.bmj.com/ transient headaches, vomiting and altered sulfonated immunoglobulin preparation for intravenous administration. European J Paediatr 1981;136:167-71. consciousness associated with fevers and rigors 3 Warrier I, Lusher JM. Intravenous gammaglobulin treat- in a small percentage of patients.23 To our ment for chronic idiopathic thrombocytopenic purpura in children. Am J Med 1984;76 (suppi 3A): 193-8. knowledge, however, aseptic meningitis has 4 Kato E, Shindo S, Eto Y, et al. Administration of immune been reported on only one previous occasion. globulin associated with aseptic meningitis. JAMA 1988;259:3269-71. Kato et al described a two year old child with 5 Gibson J, Laird PP, Joshua DE, et al. Very high dose ITP who developed this complication follow- intravenous gammaglobulin in thrombocytopenia ofpreg-

nancy.Aust NZ JMed 1988;18:151-3. on September 25, 2021 by guest. Protected copyright. ing the use of two different immunoglobulin 6 Robertson DM, Hosking CS, Efthimiou H, et al. Decreased preparations; immunoglobulin prepared with incidence of adverse infusion reactions in hypo- gammaglobulinaemic children receiving low pH intra- polyethylene glycol and a sulphonated prepara- venous immunoglobulin. Aust NZ J Med 1987;17: tion.4 A co-existent significant peripheral blood 495-500. 7 Kremer I, Ritz R, Brunner F. Aseptic meningitis as an eosinophilia suggested a possible allergic reac- adverse effect of co-trimoxazole. N Engl J Med tion. Neither of our cases, however, showed an 1983;308:1481. 8 Sergent JS, Lockskin M. Azathioprine-induced meningitis eosinophilia during the episode of meningitis. in systemic erythematosus. JAMA 1978;240:529. It is conceivable that our cases may have had 9 Dyck PJ. Intravenous immunoglobulin in chronic inflam- matory demyelinating polyradiculoneuropathy and in coincidental viral aseptic meningitis. Arguing neuropathy associated with IgM monoclonal gammo- against this possibility were the absence of pathy ofunknown significance. Neurology 1990;40:327-8.