Drug-induced Aseptic Meningitis: An Uncommon, Challenging Diagnosis

Mark M. Bai, MDResident

Associate Clinical Professor

Residency Program

Fontana, Calif

Drug-induced aseptic meningitis is an uncommon and mysterious adverse reaction to some commonly used medications. This condition can mimic the signs and symptoms of a true infectious meningitis. This article provides a concise summary of drug-induced aseptic meningitis, outlining the challenges a primary care physician may face in making the clinical diagnosis. An illustrative case highlights the role of trimethoprim/sulfamethoxazole in the pathogenesis of aseptic meningitis. Although trimethoprim/sulfamethoxazole is the most common antibiotic associated with drug-induced aseptic meningitis, to date only 27 cases have been described in the literature.

PRACTICE POINTS

• NSAIDs account for most cases of drug-induced aseptic meningitis, especially in patients with SLE or other connective tissue disorders.
• Classic signs and symptoms of meningitis generally develop within 24 hours of drug ingestion, although it may take days.
• Drug-induced aseptic meningitis can mimic the clinical features of infectious meningitis.

Drug-induced aseptic meningitis is a rare but important and often-challenging diagnosis for the primary care physician. It has been well described in the literature, most frequently in association with medications such as nonsteroidal antiinflammatory drugs (NSAIDs), intravenous (IV) immunoglobulins, intrathecal medications, or antibiotics.

The first documented case of drug-induced aseptic meningitis was reported in 1963 in a patient who had taken 2 tablets of sulfamethizole.¹ The advent of ibuprofen (eg, Advil, Motrin) in the 1970s significantly increased the incidence of drug-induced aseptic meningitis, especially in patients with systemic lupus erythematosus (SLE) or other rheumatic autoimmune disorders. As a result, the term "Motrin meningitis" became popular. NSAIDs still account for most cases, although similar reactions to other drugs have been described in the literature involving patients of all ages, with or without preexisting conditions (Table). Trimethoprim/sulfamethoxazole (TMP/SMX; Bactrim, Cotrim, Septra) is the antibiotic most frequently associated with drug-induced aseptic meningitis, yet only 27 such cases have been documented in the literature.^2-4

Pathogenesis

There are 2 proposed mechanisms for drug-induced aseptic meningitis. The first mechanism is a direct chemical irritation of the meninges by intrathecal agents. The second, which applies to nonintrathecal medications, is not as well understood. It is based on the assumption that drug-induced aseptic meningitis is an acute hypersensitivity reaction involving the meninges and is supported primarily by circumstantial evidence that includes the temporal relationship between drug ingestion and development of symptoms, the progressively shorter incubation periods in recurrent cases, the development of classic hypersensitivity features, and the rapid resolution of symptoms after the drug is discontinued. Connective-tissue diseases, in particular SLE, appear to be a risk factor for drug-induced aseptic meningitis. The link between the 2 conditions does not seem coincidental, given that many healthy individuals have used NSAIDs without developing drug-induced aseptic meningitis. This link is also consistent with a type III hypersensitivity mechanism, which specifically involves the formation of antibody complexes with the offending drug, and SLE is an immune complex-mediated disease.⁴ More research is needed to fully understand the pathogenesis of drug-induced aseptic meningitis.

Diagnosis

Signs and symptoms generally develop within 24 hours of drug ingestion, although it may sometimes take days. The patient often exhibits the classic symptoms of meningitis, including headaches, fevers, neck stiffness, mental status changes, malaise, nausea, vomiting, chills, generalized arthralgias, and myalgias. Characteristics of a hypersensitivity reaction may also be present, such as skin rash, pruritis, conjunctivitis, facial edema, photophobia, or papilledema. Classic signs of meningitis on physical examination may also be seen, including nuchal rigidity, and Kernig's and Brudzinski's signs.⁵ Thus, differentiating this condition from infectious meningitis is crucial.

Laboratory test results may show a normal or elevated peripheral white blood cell (WBC) count, so blood tests are not diagnostic. A lumbar puncture usually reveals an elevated opening pressure and cerebrospinal fluid (CSF) pleocytosis ranging from hundreds to several thousands of WBCs, although counts as low as 8 WBCs have been documented.^6,7 Polymorphonuclear cells generally predominate, but a few cases of lymphocytic and eosinophilic drug-induced aseptic meningitis have been documented.^6,8,9 CSF glucose levels are usually normal or decreased, and protein levels are usually elevated. All cultures, including CSF cultures, must be negative for any bacterial, viral, or fungal etiologies.

Imaging studies are usually unnecessary. Magnetic resonance imaging scans of the brain have revealed mild meningeal enhancement and supratentorial white-matter T₂ abnormalities, which resolved after discontinuing the offending medication.¹⁰

Drug-induced aseptic meningitis is a diagnosis of exclusion that is made after infectious causes have been ruled out. A temporal relationship between the use of the drug and subsequent onset of meningeal symptoms, negative CSF culture, and resolution of symptoms after drug withdrawal allow for a presumptive diagnosis.

It is important to note that symptoms may take days to develop after the first exposure to the drug - in one case, symptoms occurred after 4 days of amoxicillin (Amoxil, Trimox) treatment.¹¹ In fact, some patients initially tolerate the offending drug without complications.¹⁰ Repeat exposures to the drug, however, will always demonstrate a quicker onset of symptoms, usually within hours.^2,3,10 Thus, a definitive diagnosis can be made, if necessary, with a drug rechallenge in a controlled setting.

Treatment

Treatment of drug-induced aseptic meningitis consists of discontinuing the suspected medication and supportive measures. Most meningeal signs and symptoms resolve within 24 to 48 hours of stopping the offending drug.⁵ In-hospital observation and treatment with IV antibiotics is appropriate until bacterial meningitis has been ruled out. The prognosis is excellent, typically with complete reversal of symptoms and no evidence of residual effects. There have been no documented fatalities to date.

Illustrative Case

A 41-year-old man with no notable medical history presented to the emergency department complaining of headache and neck stiffness. Approximately 2 weeks earlier he saw a physician for a sore throat and ear infection and was prescribed TMP/SMX and a decongestant (chlorpheniramine/pseudoephedrine). His condition improved until about 8 days later, when he began to have fever up to 102?F and nonspecific chest pain. After an evaluation by another physician, he stopped the TMP/SMX as instructed. The fever resolved, but during the next 2 days he developed a headache, stiff neck, night sweats, nausea, photophobia, diffuse arthralgias, and generalized, nonpruritic skin redness. The patient denied any previous allergies to medications. He also denied taking TMP/SMX before this recent illness.

On admission, he was in mild distress secondary to generalized pain but was alert and oriented. The patient was mildly tachycardic (pulse, 105 beats/min), but his vital signs were otherwise unremarkable. The patient was wearing dark glasses because of photophobia, and his soft palate and posterior pharynx were erythematous with a few shallow ulcers. His neck was moderately rigid, and he was unable to flex or extend his neck secondary to pain that radiated to the back. Some of his anterior cervical lymph nodes were tender and palpable bilaterally. Other systems were normal, as were imaging studies.

Laboratory test results on admission included a normal complete blood cell count and a normal chemistry panel. Urinalysis results were also unremarkable. A lumbar puncture with CSF analysis revealed: 8 WBCs/mm³, with 100% monocytes; 3 red blood cells/mm³; glucose, 48 mg/dL; protein, 30 mg/dL; lactate, 11 mg/dL. Results of the CSF bacterial cultures were negative.

The patient was started empirically on IV ceftriaxone sodium (Rocephin), 2 g every 12 hours before culture results were obtained. He required IV hydromorphone HCl (Dilaudid) and morphine sulfate (eg, Astramorph, Duramorph, Infumorph) initially for pain control. The patient's clinical course improved quickly during his next 2 days in the hospital. The ceftriaxone was stopped, and the patient was discharged home with oral medications for pain and instructions for outpatient follow-up. He was told to avoid TMP/SMX in the future. There were no residual effects or further episodes over 9 months of follow-up.

Our patient did not have the typical features of drug-induced aseptic meningitis. There was a temporal relationship between the ingestion of TMP/SMX and the onset of aseptic meningitis, but his incubation period was about 10 days, notably longer than the usual 24 hours, even with first exposure to a medication. Also, he stated he had stopped the medication for 2 days before the onset of significant meningeal symptoms. Similar atypical cases have been described in the literature,^10,11 but they are the minority.

It is possible that our patient had a viral meningitis, especially given his throat ulcerations and viral-like syndrome. The CSF showed only 8 WBCs, however, which is much lower than expected both in viral meningitis and in drug-induced aseptic meningitis. In addition, his signs and symptoms of meningitis ended relatively abruptly, which would be more unusual in a viral syndrome than in a drug-induced case. If it were absolutely necessary to make a definitive diagnosis, a controlled drug rechallenge would have been appropriate. Alternatively, it was determined more appropriate to advise the patient to avoid use of TMP/SMX in the future.

Conclusion

Drug-induced aseptic meningitis must always be considered in the differential diagnosis of a patient presenting with acute or recurrent symptoms and signs of meningitis, especially after infectious causes have been ruled out. Although the syndrome is well documented in the literature, the exact pathogenesis is still unknown. Drug-induced aseptic meningitis can affect any patient population, but it is more common in those with SLE or with other autoimmune rheumatic diseases. A wide variety of medications can be responsible for this condition, so a careful medication history, including the temporal relationship between drug use and onset of symptoms, must be obtained. The successful withdrawal of the offending agent helps support this often-difficult diagnosis of exclusion. The syndrome usually resolves quickly once the culprit has been removed.

SELF-ASSESSMENT TEST

1. Which of these drug classes is most likely to be associated with drug-induced aseptic meningitis?

• Antibiotics
• IV immunoglobulins

2. Which of the following laboratory values is least consistent with a drug-induced aseptic meningitis diagnosis?

• Elevated CSF protein
• Elevated peripheral WBC count

3. All these statements about drug-induced aseptic meningitis are true, except:

• Connective-tissue disease increases risk
• Signs and symptoms usually develop within 24 hours of drug ingestion

4. Which of the following presenting features is NOT associated with drug-induced aseptic meningitis?

• Conjunctivitis
• Epiphora

5. Which of these medications is least likely to induce aseptic meningitis?

• Sulfadiazine
• Ciprofloxacin

(Answers at end of reference list)

N Engl J Med.

1. Barrett PV, Thier SO. Meningitis and pancreatitis associated with sulfamethizole. 1963;268:36-37.

Neurology.

2. Davis BJ, Thompson J, Peimann A, et al. Drug-induced aseptic meningitis caused by two medications. 1994;44:984-985.

Drug Saf.

3. Jolles S, Sewell WA, Leighton C. Drug-induced aseptic meningitis: diagnosis and management. 2000;22:215-226.

Clin Nephrol.

4. Muller MP, Richardson DC, Walmsley SL. Trimethoprim-sulfamethoxazole induced aseptic meningitis in a renal transplant patient. 2001;55:80-84.

Postgrad Med

5. Chaudhry HJ, Cunha BA. Drug-induced aseptic meningitis. Diagnosis leads to quick resolution. . 1991;90:65-70.

Arch Intern Med.

6. Moris G, Garcia-Monco JC. The challenge of drug-induced aseptic meningitis. 1999;159:1185-1194.

Lancet.

7. Gilroy N, Gottlieb T, Spring P, et al. Trimethoprim-induced aseptic meningitis and uveitis. 1997;350:112.

Am J Med.

8. Asperilla MO, Smego RA Jr. Eosinophilic meningitis associated with ciprofloxacin. 1989;87:589-590.

Neurology

9. Quinn JP, Weinstein RA, Caplan LR. Eosinophilic meningitis and ibuprofen therapy. . 1984;34:108-109.

Pediatrics.

10. Redman RC, Miller JB, Hood M, et al. Trimethoprim-induced aseptic meningitis in an adolescent male. 2002;110:e26.

Neurology

11. Wittmann A, Wooten GF. Amoxicillin-induced aseptic meningitis. . 2001;57:1734.

Answers: 1. C; 2. A; 3. C; 4. D; 5. D