Ibuprofen-induced aseptic meningoencephalitis

R. Z. Lee, O. Hardiman1 and P. G. O'Connell

Departments of Rheumatology and
1 Neurology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland

SIR, We report the case of a 69-yr-old man, previously healthy, who became nauseated, agitated, confused and pyrexic on two occasions, within hours of consumption of ibuprofen. A diagnosis of ibuprofen-induced aseptic meningoencephalitis was made based on the patient's typical clinical and laboratory findings, the close temporal association with ibuprofen ingestion and the rapid resolution of symptoms despite discontinuation of antibiotic treatment on the latter episode. Rheumatologists should be aware of this rare but dramatic complication of a common medication.

A previously healthy 69-yr-old man presented via the Casualty Department in June 1998 with acute onset of agitation, confusion and expressive dysphasia. There was no antecedent history. Prior to admission, he complained of headaches. Approximately 6 h later, he became agitated and confused.

On examination, positive findings included a pyrexia of 39.0°C, a petechial rash on his abdomen and arms and bilateral extensor plantar responses. He was treated empirically with intravenous benzylpenicillin and cefotaxime. A computer-aided tomography (CAT) scan of his brain was normal. Lumbar puncture showed leucocytosis, with 60% monocytes, elevated proteins, normal glucose (see Table 1Go) and no malignant cells. There was no growth of organisms from cerebrospinal fluid (CSF) cultures, blood cultures and skin scrapings. Meningococcal PCR, Ziehl Neelsen stain, viral and atypical serology were all negative.


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TABLE 1.  CSF findings

 
An electroencephalogram showed theta activity in the temporal leads. Therapy was broadened to include intravenous acyclovir, ampicillin and gentamicin. He required intubation and assisted ventilation for 2 days and then gradually recovered over several days. A repeat lumbar puncture showed persistent leucocytosis and elevated CSF pressure with reduced CSF proteins (see Table 1Go). He was discharged with a diagnosis of meningoencephalitis of unknown aetiology. Before discharge, the patient reported he had consumed ibuprofen 400 mg for pain in his foot, some hours prior to the onset of his symptoms.

Three months later, he was reviewed by one of the authors (POC). He was well apart from right foot pain. Shortly after review, he ingested 400 mg of ibuprofen and within 30 min developed nausea, vomiting, profuse sweating, headaches, fever and a petechial rash on his body. Approximately 9 h later he became drowsy and agitated and was found to have bilateral up-going plantar reflexes. A CAT scan of his brain was normal. A lumbar puncture showed elevated proteins and white cells, predominantly neutrophils (see Table 1Go). He received intravenous antibiotics, but these were discontinued after 48 h when blood and CSF cultures revealed no growth. He was commenced on high-dose dexamethasone and his confusional state resolved within 48 h. He remained ataxic and uncoordinated for a further week. A subsequent magnetic resonance imaging scan of the brain was normal. His serum immunoglobulins, eosinophil count and complement levels were normal. Antinuclear antibodies and rheumatoid factor were negative. On both occasions the serum white cell count was elevated at 13.5 and 13.3, respectively, with neutrophilia of 12.0 and 10.0. The erythrocyte sedimentation rate was 14 mm/h. Liver and renal profiles were normal.

Aseptic meningitis has been reported rarely following ingestion of ibuprofen. The first case was described in 1978 by Widener and Littman [1] who reported the case of a 26-yr-old woman with systemic lupus erythematosus (SLE) who presented with chills, fever, headaches and meningism after ingestion of ibuprofen on four separate occasions. CSF analysis showed evidence of aseptic meningitis. This case was confirmed with a drug re-challenge. Since then, a Medline search of all English literature over the past 10 yr has revealed 34 additional cases. The majority of these cases occurred in patients with underlying rheumatic diseases, particularly in SLE [2], but also in mixed connective tissue disorders [3] and rheumatoid arthritis [4]. However, it has also been seen, as in our case, in previously healthy individuals [5] (11 of 35 cases; 31.4%). Although ibuprofen is the non-steroidal anti-inflammatory drug (NSAID) most frequently involved in drug-induced aseptic meningitis, sulindac [6], tolmetin [7], naproxen [8] and diclofenac [9] have also been implicated.

The signs and symptoms of ibuprofen-induced meningitis often begin from a few minutes to several hours post-ingestion [10]. Common features include fever, shaking chills, headache, vomiting, generalized arthralgia/myalgia, nuchal rigidity, rash, abdominal pain and confusion. The condition is usually described as an aseptic meningitis. However, several cases, including ours, strongly suggest that the description of meningoencephalitis is more appropriate in view of the presence of confusion and up-going plantar reflexes. CSF findings in ibuprofen-induced aseptic meningitis vary. The pressure is raised with an elevated protein concentration, normal glucose level and polymorphonuclear pleocytosis, unlike that of SLE-induced aseptic meningitis which is usually lymphocytic [10]. In our patient, the CSF showed a different morphology of cells on the two separate occasions; one predominantly monocytes and the other predominantly polymorphonuclear. The serum white cell count may be normal or elevated.

Diagnosis is by exclusion of an infectious agent and other non-infectious causes such as central nervous system tumours, metastatic carcinomas, sarcoidosis, SLE and granulomatous angiitis, and by demonstrating a convincing temporal relationship between the time of ingestion of drugs and the onset of the patient's symptoms. The recurrence of symptoms after re-challenge strongly supports the diagnosis of drug-induced aseptic meningitis. Our patient developed a nearly identical clinical picture consistent with meningoencephalitis on two separate occasions shortly after the consumption of ibuprofen. Although his recovery was fairly rapid, the process was still active 5 days later (see Table 1Go, first admission). He had not been re-challenged deliberately due to the severity of his symptoms, although he was re-challenged inadvertently during the second episode.

In summary, NSAID-induced aseptic meningoencephalitis is an extremely rare occurrence, but it is important for physicians, particularly rheumatologists, to be alert to the possibility of this dramatic adverse effect of such a widely prescribed medication.

Notes

Correspondence to: P. G. O'Connell. Back

References

  1. Widener HL, Littman BH. Ibuprofen-induced meningitis in systemic lupus erythematosus. J Am Med Assoc1978;239:1062–4.[Abstract]
  2. Wasner CK. Ibuprofen, meningitis and systemic lupus erythematosus. J Rheumatol1978;5:162–4.[ISI][Medline]
  3. Agus B, Nelson J, Kramer N, Mahal SS, Rosenstein ED. Acute central nervous system symptoms caused by ibuprofen in connective tissue disease. J Rheumatol1990;17:1094–6.[ISI][Medline]
  4. Horn AC, Jarrett SW. Ibuprofen-induced aseptic meningitis in rheumatoid arthritis. Ann Pharmacother1997;31:1009–11.[Abstract]
  5. Lawson JM, Grady MJ. Ibuprofen-induced aseptic meningitis in a previously healthy patient. West J Med1985;143:386–7.[ISI][Medline]
  6. Ballas ZK, Donta ST. Sulindac-induced aseptic meningitis. Arch Intern Med1982;142:165–6.[Abstract]
  7. Ruppert GB, Barth WF. Tolmetin-induced aseptic meningitis. J Am Med Assoc1981;245:67–8.[Abstract]
  8. Weksler BB, Lehany AM. Naproxen-induced recurrent aseptic meningitis. Ann Pharmacother1991;25:1183–4.[Abstract]
  9. Codding C, Targoff IN, McCarty GA. Aseptic meningitis in association with diclofenac treatment in a patient with systemic lupus erythematosus. Arthritis Rheum1991;34:1340–1.[ISI][Medline]
  10. Hoppmann RA, Peden JG, Ober SK. CNS side effects of NSAIDs. Aseptic meningitis, psychosis and cognitive function. Arch Intern Med1991;151:1309–13.[Abstract]
Accepted 17 September 2001





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