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MENINGITIS

A Differential Diagnosis of Drug-Induced Aseptic

Clair Cascella, MD, Sara Nausheen, MD, and Burke A. Cunha, MD

Drug-induced aseptic meningitis should be included in the are directly irritated by the differential diagnosis of viral/aseptic meningitis. Clinicians intrathecal administration of drugs. should use historical clues in patients presenting with signs and The other is that the meninges are symptoms of to aid in the differentiation of expressing an immunological hyper- drug-induced aseptic meningitis from other causes of aseptic sensitivity—most often a type 3 or type 4 hypersensitivity reaction—to meningitis. Viruses are the most common cause of aseptic 2 meningitis, with being the most common among the offending drug. An association between hyper- viruses in cases presenting as aseptic meningitis. Ibuprofen is sensitivity reactions and underlying currently the most common cause of drug-induced aseptic collagen-vascular disease or rheu- meningitis. Drug-induced aseptic meningitis is a benign con- matological disease has been report- dition without long-term sequelae. The diagnosis of drug- ed.1-10 Typically, the cerebrospinal induced aseptic meningitis is made by establishing a causal fluid (CSF) profile in drug-induced relationship between the use of the drug and the onset of signs aseptic meningitis is that of a neu- and symptoms, supported by negative tests for infectious trophilic pleocytosis accompanied causes of symptoms and rapidity of resolution after the drug by a normal CSF lactic acid level is discontinued. [Infect Med. 2008;25:331-334] and a variably elevated CSF protein level.1,3 Patients who have drug- induced meningitis may have eo- Key words: Drug-induced aseptic meningitis Enteroviral meningitis sinophils present in the CSF (fewer than 5%). septic meningitis refers to a ticularly if aseptic meningitis de- nonbacterial inflammation of velops in association with the use of THE CLINICAL PICTURE A the leptomeninges.1 Viruses NSAIDs or other offending drugs Patients who have drug-induced are the most common cause of asep- (Table 1) and if clinical recovery is aseptic meningitis typically present tic meningitis, and the most common rapid following cessation of the drug with fever, headache, and nuchal viruses that cause aseptic meningitis or if results of viral studies are rigidity. Signs and symptoms usual- are enteroviruses. Drug-induced negative. ly appear within 24 to 48 hours after aseptic meningitis is rare but proba- The pathogenetic mechanisms of drug ingestion, but symptoms may bly more common than the literature drug-induced aseptic meningitis are not occur until 2 years post-thera- would suggest; therefore, it should not fully understood, but 2 major py.2,6 Drug-induced aseptic meningi- be included in the differential diag- mechanisms have been proposed. tis may develop in a patient who ini- nosis of aseptic meningitis, par- One proposed mechanism is that the tially was able to tolerate the caus- ative drug.1,6 In patients who have drug-in- Dr Cascella is a first-year medical resident in the department of medicine at Winthrop-University duced aseptic meningitis, the typical Hospital in Mineola, NY. Dr Nausheen is a second-year fellow in the infectious disease division at CSF profile reveals a neutrophilic Winthrop-University Hospital. Dr Cunha is chief of the infectious disease division at Winthrop- University Hospital and professor of medicine at State University of New York School of Medi- pleocytosis, with several hundred to cine in Stony Brook. several thousand white blood cells

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Table 1 – Medications known to cause aseptic meningitis Medications Common Uncommon Rare NSAIDs Ibuprofen Sulindac Ketoprofen Naproxen Salicylatesa Diclofenac Tolmetin Rofecoxib Piroxicam Celecoxib Antimicrobials Trimethoprim/ Sulfonamides Cephalosporins sulfamethoxazole Penicillin Trimethoprim Amoxicillin Amoxicillin/clavulanate Isoniazid Ciprofloxacin Metronidazole Pyrazinamide Valacyclovir Indinavir Ornidazole Immunomodulating agents Monoclonal Azathioprine Levamisole antibody OKT3 Efalizumab Intravenous IgG Infliximab Sulfasalazine Intrathecal agents Metrizamide Methotrexate Cytarabine Gentamicin Methylprednisolone Iophendylate acetate Iopamidol Iohexol Hydrocortisone Baclofen Gadolinium Diethylenediamine pentaacetic acid Spinal anesthesia Other Carbamazepine Monovalent and rubella vaccine Hepatitis B vaccine Ranitidine Famotidine Dexchlorpheniramine Phenazopyridine Radiolabeled albumin Lamotrigine Allopurinol Pentoxifylline Methotrexate

a With serum levels ! 70 mg/dL. Adapted from Hopkins S, Jolles S. Expert Opin Drug Saf. 20053; Marinac J. Ann Pharmacother. 1992.4

per microliter; normal glucose lev- may occur. Drug-induced aseptic DIFFERENTIAL DIAGNOSIS els; and variably elevated protein meningitis is reversible, with most The differential diagnosis of aseptic levels.1,2,4-7 Results of CSF Gram stain signs and symptoms resolving with- meningitis is extensive and includes and cultures are negative, and lym- in 24 to 48 hours after the drug infectious and noninfectious causes phocytic or eosinophilic pleocytosis is discontinued.2,4-7 (Table 2).1-10 Drug-induced aseptic

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Table 2 – Causes of acute aseptic meningitis Common Uncommon Rare

Infectious causes Bacterial Treponema pallidum Borrelia recurrentis infection (relapsing fever) Mycobacterium Mycoplasma pneumoniae Spirillum minus infection tuberculosis infection infection (rat-bite fever) Subacute bacterial Rocky Mountain Nocardiosis endocarditis spotted fever Actinomyces infection Parameningeal infection Brucellosis (epidural subdural Ehrlichiosis abscess, sinus or ear infection) Partially treated bacterial meningitis Viral Echovirus infection Epstein-Barr virus Parainfluenza virus infection infection infection Rotavirus infection Mumps Adenovirus infection Vaccinia virus infection St Louis encephalitis infection West Nile virus infection Eastern equine encephalitis Varicella Human herpesvirus 6 infection Western equine encephalitis Measles Japanese B encephalitis California encephalitis Rubella Murray Valley encephalitis virus type 1 infection type 2 infection HIV infection Lymphocytic choriomeningitis Poliovirus infection Fungal Candidiasis Blastomycosis Histoplasmosis Aspergillosis Sporotrichosis Parasitic Angiostrongylus Cysticercosis cantonensis infection Trichinella spiralis infection Toxoplasmosis

Noninfectious causes Neoplastic diseases Intracranial tumors Lymphoma Leukemia Metastatic carcinomas Systemic diseases Vogt-Koyanagi-Harada Behçet disease syndrome Systemic Sjögren syndrome erythematosus Rheumatoid arthritis Neurosurgical Neurosurgery (posterior procedures fossa syndrome) Intrathecal agents Medications See Table 1

Adapted from Chaudhry HJ, Cunha BA. Postgrad Med. 19911; Connolly KJ, Hammer SM. Infect Dis Clin North Am. 1990.8

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meningitis is a diagnosis of exclu- distinguishing bacterial from a drug- 10. Kepa L, Oczko-Grzesik B, Stolarz W, Sobala- Szczygiel B. Drug-induced aseptic meningitis sion. It is important to obtain a histo- induced aseptic meningitis because in suspected infections. ry of medical disorders such as sys- CRP levels are usually highly elevat- J Clin Neurosci. 2005;12:562-564. 11. Bonnel RA, Villalba ML, Karwoski CB, Beitz J. temic lupus erythematosus, the most ed in bacterial meningitis compared Aseptic meningitis associated with rofecoxib. frequent underlying condition asso- with drug-induced aseptic meningi- Arch Intern Med. 2002;162:713-715. 2,5 12. Papaioannides DH, Korantzopoulos PG, Giotis ciated with drug-induced aseptic tis. The diagnosis of drug-induced CH. Aseptic meningitis possibly associated meningitis.7 It is also important to aseptic meningitis is made by estab- with celecoxib. Ann Pharmacother. 2004;38:172. 13. Wittmann A, Wooten GF. 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