Here's an interesting Case Report....

[Ace844]

Hello Everyone,

I saw this interesting case report and thought you all may be interested in reading it as it is about a situation which I think few of us consider as a possible etiology of this disorder...

HTH,

ACE844

(Characteristics of Meningitis Caused by Ibuprofen: Report of 2 Cases With Recurrent Episodes and Review of the Literature

Rodríguez @ Susana Casas MD; Olguín, Adriana Manzur MD; Miralles, Carmen Peña MD; Viladrich, Pedro Fernández MD

From Infectious Diseases Service (SCR, AMO, CPM, PFV), Hospital Universitari de Bellvitge, L'Hospitalet del Llobregat; and University of Barcelona (PFV), Barcelona, Spain.

Address reprint requests to: Dr. Pedro Fernández Viladrich, Hospital Universitari de Bellvitge, Feixa Llarga s/n 08907, L'Hospitalet del Llobregat, Barcelona, Spain. Fax: 0034-93-260-76-37; e-mail: pfviladrich@csub.scs.es.)

Abstract

Abstract: Ibuprofen is a common nonsteroidal antiinflammatory drug that is the most frequent cause of aseptic meningitis induced by drugs. The incidence of this type of aseptic meningitis is increasing, mainly among patients with underlying autoimmune connective tissue disorder, but also among healthy people. We report 2 patients with recurrent meningitis caused by ibuprofen mimicking bacterial meningitis: the first patient a woman with dermatomyositis and the second patient a previously healthy woman who developed autoimmune thyroiditis a few months later.

We then review 71 episodes of ibuprofen-related meningitis in 36 patients reported in the literature. Twenty-two patients (61%) presented with an autoimmune connective tissue disorder, mainly systemic lupus erythematosus, and 22 (61%) had recurrent episodes. Most episodes consisted of an acute meningeal syndrome with a predominance of neutrophils in cerebrospinal fluid (CSF) in 72.2% of episodes and elevated protein in the CSF, so the clinical presentation of this type of aseptic meningitis may be quite similar to that of acute bacterial meningitis. CSF glucose levels are usually normal, which may help to differentiate between these 2 types of meningitis. In some cases the clinical presentation is that of meningoencephalitis with neurologic focal deficits.

Although based on the close relation between the administration of ibuprofen and the onset of symptoms, especially if previous episodes have occurred, the diagnosis of ibuprofen-induced aseptic meningitis is a diagnosis by exclusion. If the clinical picture is compatible with bacterial meningitis, empirical antibiotic therapy must be administered until negativity of cultures and other microbiologic tests is determined. Rechallenge to ibuprofen reproduces the symptoms and confirms the diagnosis, but is usually not advised.

Whatever the clinical presentation, physicians must consider the possibility of ibuprofen-related meningitis or meningoencephalitis in patients taking ibuprofen, especially if they are suffering from an autoimmune connective tissue disorder. On the other hand, we think it would be appropriate to screen for autoimmune disease in previously healthy patients diagnosed with ibuprofen-related meningitis or meningoencephalitis. Finally, we propose that meningitis due to ibuprofen be included in the list of causes of recurrent aseptic meningitis.

INTRODUCTION

Ibuprofen, a nonsteroidal antiinflammatory drug (NSAID) of the propionic acid group, is frequently used in patients with connective tissue disorders 16, and its use in patients without underlying diseases has progressively increased in the last years 25. Aseptic meningitis is a rare 31, albeit well-known, adverse effect of ibuprofen, and sporadic cases of patients with unique or recurrent episodes considered to be caused by this drug have been reported. In fact, it is the leading cause of aseptic meningitis induced by drugs 36. However, to our knowledge a comprehensive review of the characteristics of this type of meningitis has never been published.

We have recently seen 2 patients with recurrent episodes of meningitis induced by ibuprofen that mimicked bacterial meningitis, so they were hospitalized in an infectious disease ward. The diagnosis was reached by a rechallenge with the drug, thereby assuring accuracy. These cases have prompted us to review the literature to establish the clinical and biologic characteristics of this type of meningitis.

CASE REPORTS

Case 1

A 57-year-old woman with Sjögren syndrome and primary dermatomyositis presented in May 2003 with headache lasting 12 hours, nausea and vomiting, and without fever some hours after taking a tablet of ibuprofen. Physical findings, neurologic examination, computerized tomography (CT) of the brain, blood cell counts, and routine chemical serum determinations were all normal. Lumbar puncture revealed turbid cerebrospinal fluid (CSF) with opening pressure of 25 cm H2O. CSF cytochemical analysis showed 800 white blood cells (WBC)/mm3 (of which 85% were neutrophils and 15% lymphocytes), 372 mg/dL protein, and 57 mg/dL glucose. CSF Gram stain and culture were negative, and CSF pneumococcal antigen (Binax) was also negative. Empirical intravenous therapy with ceftriaxone and ampicillin was initiated and maintained for 10 days. The patient showed a rapid clinical response and was discharged without any apparent sequelae.

Three months later she was readmitted with similar symptoms beginning 12 hours after resumption of ibuprofen. This time neck stiffness was present. CSF was turbid with opening pressure of 24 cm H2O, WBC count of 1000/mm3 (90% neutrophils and 10% lymphocytes), 300 mg/dL protein, and 54 mg/dL glucose. CSF Gram stain was negative. Empirical intravenous antibiotic therapy was again administered but withdrawn 3 days later when blood and CSF cultures showed no microbial growth, and the patient was diagnosed with aseptic meningitis induced by ibuprofen. Her clinical symptoms improved shortly after admission, and the patient was discharged without symptoms.

Case 2

A previously healthy 49-year-old woman was admitted in October 2004 due to vertiginous syndrome lasting 5 days and headache, nausea, and vomiting a few hours before admission. On examination, positive findings included minimal pyrexia of 37.2 °C axillary temperature, confusion, horizontal nystagmus, and nuchal rigidity. WBC count was 27,120 cells/mm3 with neutrophilia. CSF was opalescent with opening pressure of 18 cm H2O and 2190 leukocytes/mm3 (76% neutrophils, 18% histiocytes, and 6% lymphocytes), 336 mg/dL protein, and 77.4 mg/dL glucose. CSF stains and cultures for bacteria, mycobacteria, and fungi were negative. CSF cryptococcal antigen and syphilis serology were also negative. She was treated empirically with intravenous ceftriaxone and ampicillin for 10 days. The patient recovered consciousness and meningeal signs disappeared but recovery from the vertiginous syndrome was slow. CSF obtained on day 8 was clear, with normal opening pressure and 315 leukocytes/mm3 (44% neutrophils, 2% histiocytes, and 54% lymphocytes), 178 mg/dL protein, and 63 mg/dL glucose. CSF bacterial cultures were negative. A CT of the brain was unremarkable.

On day 12 of hospitalization the patient was given a dose of ibuprofen for cervical pain, and 2 hours later, an abrupt onset of headache, fever of 39 °C, and vomiting occurred. On examination she was somnolent and confused, and neck stiffness and Kerning and Brudzinski signs were present. A lumbar puncture was not performed, and symptoms resolved promptly after ibuprofen was discontinued and corticosteroids were initiated. It was then that the patient reported that she had taken a dose of 400 mg ibuprofen 24 h before admission. She was discharged without sequelae, and a diagnosis of recurrent aseptic meningitis caused by ibuprofen. Four months later, she was diagnosed with autoimmune thyroiditis.

LITERATURE REVIEW METHODS

We conducted a MEDLINE (National Library of Medicine, Bethesda, MD) search with the subject headings "meningitis," "aseptic meningitis," "meningoencephalitis," "encephalitis," and "ibuprofen," to identify pertinent literature and case reports of aseptic meningitis or meningoencephalitis induced by ibuprofen published up to June 2005. We limited our search to the English and French literature available to us, with a few exceptions in other languages. All patient data we show were extracted from the reports we found, but sometimes not all clinical or laboratory data were detailed in the articles. We excluded all cases in which meningitis could not be related to ibuprofen 15,25,37,44,49. We have compiled the clinical and biologic characteristics of the 71 reported episodes of aseptic meningitis induced by ibuprofen.

RESULTS

We analyzed 71 episodes of aseptic meningitis induced by ibuprofen that occurred in 36 patients 1-3,5,8,9,11,12,14,16-21,23,24,27,29,30,32,33,35,37,39,41,42,44-46,49-53. There were 23 women (64%). The median age of the patients was 41 years (range, 21-74 yr). Twenty-two patients (61%) had recurrent episodes of aseptic meningitis after repeated ibuprofen ingestion. The number of recurrent episodes ranged from 2 to 4 (Table 1)1,3,8,12,14,18,19,23,24,29,32,35,37,39,42,44,46,51-53. Twenty-two patients (61%) suffered from an underlying autoimmune connective tissue disorder: 14 (39%) systemic lupus erythematosus (SLE)9,12,16,18-20,24,29,33,35,46,50,52,53; 6 (16.6%) undifferentiated or mixed connective tissue disease 1,3,17,21,41; 1 (2.8%) rheumatoid arthritis 23; and 1 (2.8%) Sjögren syndrome 2.

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[Email Jumpstart To Image] TABLE 1. CSF Characteristics in 54* of 71 Reported Episodes of Ibuprofen-Induced Aseptic Meningitis

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The latency period between intake of ibuprofen and onset of symptoms varied but it was less than 24 hours in 36 of the 46 episodes in which this information was reported 1,3,8,9,11,12,14,18-20,23,24,27,29,30,32,37,41,42,44-46,49,50,52,53. The doses of ibuprofen the patients had taken were also variable. Twenty-five episodes developed after only 1 dose of 200-600 mg of ibuprofen 1,3,9,12,14,16,17,20,24,29,30,32,35,37,42,44,49,51-53. But in 15 episodes, the symptoms appeared after taking more than 2 doses of ibuprofen 1,2,14,19,21,27,33,39,41,42,45,46. Time from exposure to ibuprofen before developing symptoms was very short except in 8 cases: 2 cases after taking ibuprofen for 1 week 2,39, 4 for 2 weeks 14,21,42,52, 1 for "several weeks"27, and 1 for 2 years 35. It is remarkable that 1 patient with ibuprofen-induced aseptic meningitis also developed 2 different episodes of aseptic meningitis in relation to naproxen and rofecoxib 2.

The frequency of symptoms and signs is described in Table 2. Many patients had typical meningeal syndrome with fever (69%), altered mental status (58%), headache (52%), neck stiffness (46.5%), and nausea and vomiting (42%). Some patients had meningoencephalitis 1,9,12,17,32,33,42 instead of meningitis. Of note is that 9 episodes (12.7%) presented with hypotension 1,12,35,52 and 10 (14%) with cutaneous rash 12,21,24,32,33,50,52, which was petechial in 2 of them 32. Other symptoms and signs were arthralgia/myalgia 11,14,21,24,30,35,42, photophobia 2,8,9,19,27,29,30,45, blurred vision 1,11,35, conjunctivitis 1,11,21,24,30,35, abdominal pain 11,50,53, and facial edema 11,21,32. Very infrequent symptoms such as iridocyclitis 27, syndrome of inappropriate antidiuretic hormone (SIADH)41, and acute renal failure 21 were also reported. One patient progressed to coma with bilateral Babinski 32 in his 2 episodes and had to be admitted to the intensive care unit (ICU) during 1 of them. Two more patients presented with bilateral Babinski 9,17. Another 2 patients with coma 24,33, 1 of them with papilledema 24, also required admission to the ICU. Five patients developed neurologic focal deficits: palsy of conjugate movement of the eyes to the right 1, tonic-clonic movements 9,12,33 (even status epilepticus 33), and paresthesia with left hemiparesis 1. But all patients had an excellent outcome after withdrawing the drug, and none had neurologic sequelae.

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[Email Jumpstart To Image] TABLE 2. Clinical Manifestations in 71 Episodes of Ibuprofen-Induced Aseptic Meningitis

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The characteristics of the CSF found in the literature, highlighting those cases similar to bacterial meningitis, are shown in Table 1. Some reports did not show the values of these determinations and only referred to them as "normal"1,27,33,39, "increased"5, or "low"5. In 17 episodes no CSF analysis was performed 3,11,12,18,19,23,24,35,53.

The CSF pressure varied from normal to elevated up to 22.4 cm H2O, but most of the articles did not refer to this value. The WBC count in CSF was also variable with a median of 280 cells/mm3 (range, 9-5,000/mm3). The WBC differential count in CSF was as follows: predominance of neutrophils in 39 cases (39/54; 72.2%)1,3,5,8,9,12,14,17-21,23,29,30,32,35,37,41,44,46,49-53, predominance of lymphocytes in 11 (20.4%)2,24,27,33,39,42,46,53, predominance of monocytes in 2 (3.7%)8,32, and eosinophils in only 1 case (1.8%)45. In 1 case, the CSF showed 50% neutrophils and 50% monocytes 16. The median value of protein was 132 mg/dL with a range of 32-857 mg/dL. The protein level was normal in 4 cases 1,14,27,35, moderately increased (50-100 mg/dL) in 17 cases 2,8,14,21,35,39,41,42,45,46,50,52, and more significantly increased (>100 mg/dL) in 30 cases 1,3,8,9,12,16-20,23,24,29,30,32,33,37,44,49,51,53. The median value of glucose in CSF was 62 mg/dL with a range of 27-109 mg/dL. CSF glucose was slightly down in 8 cases: 10-37 mg/dL in 5 1,8,37,46,53 and reported as "low" in the other 3 5.

DISCUSSION

Central nervous system (CNS) side effects have been reported to occur in 4%-10% of patients treated with NSAIDs. The most common are headache, tinnitus, and hearing loss. Infrequent CNS side effects are aseptic meningitis, psychosis, and cognitive dysfunction 10,22,40. Ibuprofen is the most frequent cause of aseptic meningitis induced by drugs 22,26,38. However, other NSAIDs have also been recognized as causes of aseptic meningitis: diclofenac, sulindac, naproxen, ketoprofen, tolmetin, piroxicam, and, more recently, rofecoxib and celecoxib 2,4,7,22,26,38,47. The exact incidence of meningitis as a side effect of these drugs is unknown. Clinical and biologic characteristics described in cases of aseptic meningitis due to NSAIDs other than ibuprofen are similar to those of ibuprofen-induced meningitis 23.

Aseptic meningitis is a rare adverse effect of ibuprofen. In 1 population study conducted in the United States from 1977 to 1981, there was no case of aseptic meningitis among 13,230 ibuprofen users 25. The first case of ibuprofen-related meningitis was reported in 1978 by Widener and Littman 53. They described a 26-year-old woman with SLE and recurrent aseptic meningitis that was not attributed to ibuprofen until she experienced her fourth episode of meningitis.

Since then, an increasing number of cases of aseptic meningitis or meningoencephalitis attributed to this drug have been reported 1-3,5,8,9,11,12,14,16-21,23,24,27,29,30,32,33,35,37,39,41,42,44-46,49-52. Most frequently they were patients with recurrent meningitis, which in part proves that this illness is not well known and that a high level of suspicion is required for diagnosis 6,34.

The first published cases occurred in patients with underlying autoimmune connective tissue disorders, mainly SLE 36,40, but also undifferentiated or mixed connective tissue, rheumatoid arthritis, and Sjögren syndrome. Our Case 1 constitutes the first report of aseptic meningitis attributed to ibuprofen in a patient with dermatomyositis that we know of, and our second patient was diagnosed with autoimmune thyroiditis 4 months after the episode. Autoimmune thyroiditis has not been previously related to this type of ibuprofen adverse effect, either, to our knowledge. Based on the relation between autoimmune problems and aseptic meningitis related to ibuprofen, we suggest that analytical screening for such disorders should be done on previously healthy subjects with a first episode 9,33.

In addition to those cases affecting patients with autoimmune disorders, several other cases have been reported in apparently healthy people 8,11,14,27,30,32,37,39,44,45,49,51. This might be related to the broad use of NSAIDs during the past years in the general population 5,14,17,18,22,25,45 (in Spain, they are purchased over-the-counter).

The pathogenesis of this reaction remains unclear. Ibuprofen does not achieve high concentrations in CSF 8. However, it does not seem to be mediated either by inhibition of prostaglandin synthesis 8,12,14,45,53 or by the accumulation of ibuprofen's metabolites within the CNS because the latency period after rechallenge is very short, as seen in the 2 cases in the current study. Since there is increased intrathecal synthesis of IgG and immune complex formation, a specific antigen-antibody response-a type III or IV hypersensitivity reaction-confined to CNS has been suggested 3,8,14,20,28,43. Thus, a preexisting autoantibody may be activated by ibuprofen 3,8.

The higher incidence of ibuprofen-induced aseptic meningitis in patients with autoimmune disorders could be explained by the widespread use of NSAIDs or by their tendency to autoreact 48. Experimental animal studies have shown that aseptic meningitis can be induced in NZB/NZW F1 mice 1,8,14,35 (mice that develop a lupus-like disease) after administration of ibuprofen. This supports the hypothesis that these types of patients develop this side effect more frequently.

Development of aseptic meningitis is independent of the dosage of ibuprofen 39, and it is likely to occur a few hours after intake, as in our cases. So the latency period is usually very short 44. Nevertheless, patients with previous exposure to the drug days 2,14,39,42, months, or even years 35 before can develop it.

Presenting clinical manifestations of ibuprofen-related meningitis may be indistinguishable from those of acute bacterial meningitis 13,41, because of the acute onset with fever, headache, nausea and vomiting, altered mental status, and neck stiffness as usual symptoms. It is even possible to observe a cutaneous rash mimicking meningococcal disease 32.

Moreover, in the majority of cases, CSF shows pleocytosis, often very intense, with neutrophilic predominance. CSF protein levels frequently exceed those usually seen in viral meningitis. So the initial diagnosis of bacterial meningitis is quite logical in such cases. In fact, our patients presented with turbid CSF containing intense neutrophilic pleocytosis and elevated protein, so bacterial meningitis was diagnosed and antimicrobial treatment was initiated.

Occasionally, CSF may contain a significant percentage of monocytes or histiocytes, as occurred in our second patient and in other reported episodes 8,14,16,32,42,52. To our knowledge, this finding has not been described in acute bacterial meningitis, and its presence would help physicians in the diagnosis of drug-related meningitis. Likewise, a significant percentage of eosinophils 45 in CSF suggests a nonbacterial cause of meningitis.

CSF glucose levels are usually normal in ibuprofen-related meningitis, although moderate hypoglycorrhachia may occur and add to the initial suspicion of bacterial meningitis. Nevertheless, the fact that we found no case with CSF glucose levels close to 0 mg/dL or undetectable leads us to believe that this is a helpful feature in making a differential diagnosis between acute bacterial meningitis and ibuprofen-related meningitis.

There are cases that simulate viral meningitis, especially if lymphocytes predominate in CSF. The occurrence of coma and focal neurologic deficits may suggest a viral meningoencephalitis syndrome 1,9,12,17,32,33,42.

The clinical course of ibuprofen meningitis or meningoencephalitis is relatively short and benign, with rapid resolution of symptoms after discontinuing the drug 2,3,11,12,16,17,20,22,32,35,53. However, CSF may return to normality quite slowly, as illustrated in our second case, in which CSF remained altered 14 days after the onset of symptoms, as well as in other reported cases 8,16,32,53. Cognitive or neurologic sequelae have not been reported 26.

In some cases, patients have been treated with corticoids to shorten the clinical course, but, obviously, there are no comparative studies done on this 3,16,35,36. It seems rational to administer those drugs for a short period of time, especially in the most severe cases. The courses of recurrent episodes of meningitis induced by ibuprofen in the same patient were not more severe than the initial episodes 11,39, although some authors have described increased severity of symptoms 14. In our patients, characteristics of the initial episodes and the recurrences were similar. However, if an episode of ibuprofen-related meningitis is suspected, rechallenging with the drug to obtain the diagnosis is not usually indicated. Patients must be informed to avoid re-exposure not only to ibuprofen 12,16,20 but also to all drugs from the same family (dexibuprofen, dexketoprofen, flurbiprofen, ketoprofen, and naproxen). It might even be advisable to avoid the other NSAIDs that have been related to aseptic meningitis 2,22, because there are a few reports of patients with recurrent episodes of aseptic meningitis due to different NSAIDs 2,11,47.

In conclusion, although aseptic meningitis is an uncommon side effect of ibuprofen, the widespread use of ibuprofen, as well as other NSAIDs, makes an increase in its incidence a possibility. Ibuprofen is the most frequently implicated drug in aseptic meningitis induced by drugs. The clinical course of this illness may be similar to that of acute bacterial meningitis, so physicians must consider it as a differential diagnosis, mainly in patients with underlying autoimmune connective tissue disorders and in patients with recurrent meningitis. In fact, meningitis due to ibuprofen must be added to the list of causes of recurrent aseptic meningitis, and it may be appropriate to screen for autoimmune diseases in healthy subjects who develop this adverse effect.

Ibuprofen-induced aseptic meningitis is a diagnosis by exclusion that depends on the chronology between drug administration and onset of symptoms, as well as on negativity of microbiologic tests. Re-exposure to ibuprofen, often by chance, reproduces the symptoms and confirms the diagnosis, as occurred in our 2 patients. However, when the illness is compatible with acute bacterial meningitis, empirical antibiotic therapy must be administered until negativity of cultures and other antigenic or molecular tests rule out that diagnosis. This is true even if the patient has a known condition of meningitis induced by drugs.

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[AZCEP]

I'll bet it was caused by inadequate cleaning of the medication. No other reason for infections to present, right?

A bit disconcerting from a consumer's perspective, though.