REVIEW ARTICLE The Challenge of Drug-Induced Aseptic Meningitis German Moris, MD; Juan Carlos Garcia-Monco, MD everal drugs can induce the development of aseptic meningitis. Drug-induced aseptic men- ingitis (DIAM) can mimic an infectious process as well as meningitides that are secondary to systemic disorders for which these drugs are used. Thus, DIAM constitutes a diagnostic and patient management challenge. Cases of DIAM were reviewed through a MEDLINE Sliterature search (up to June 1998) to identify possible clinical and laboratory characteristics that would be helpful in distinguishing DIAM from other forms of meningitis or in identifying a specific drug as the culprit of DIAM. Our review showed that nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, intravenous immunoglobulins, and OKT3 antibodies (monoclonal antibodies against the T3 receptor) are the most frequent cause of DIAM. Resolution occurs several days after drug discon- tinuation and the clinical and cerebrospinal fluid profile (neutrophilic pleocytosis) do not allow DIAM to be distinguished from infectious meningitis. Nor are there any specific characteristics associated with a specific drug. Systemic lupus erythematosus seems to predispose to NSAID-related meningi- tis. We conclude that a thorough history on prior drug intake must be conducted in every case of meningitis, with special focus on those aforementioned drugs. If there is a suspicion of DIAM, a third- generation cephalosporin seems a reasonable treatment option until cerebrospinal fluid cultures are available. Arch Intern Med. 1999;159:1185-1194 Several drugs can induce meningitis, re- been associated with drug-induced aseptic sulting in a diagnostic and therapeutic meningitis (DIAM) (Table 1): nonsteroi- challenge. The situation becomes more dal anti-inflammatory drugs (NSAIDs),1-42 complex if the offending drug is an anti- antibiotics,43-73 intravenous immunoglobu- biotic, where the decision of withdraw- lins (IVIGs),74-99 and OKT3 monoclonal anti- ing the drug needs to be weighed against bodies (directed against the T3 receptor and, the risk of missing the treatment of an un- therefore, pan T-cell antibodies).100-119 These derlying infectious disorder. Further- drugs are frequently prescribed by differ- more, these drugs are often used to treat ent specialists (rheumatologists, neurolo- disorders that in turn may cause menin- gists, internists, etc), who should be aware gitis. Therefore, physicians should be of this problem. The internal medicine lit- aware of this possibility and a careful drug erature, however, lacks a review on this history should be obtained in every case topic. Thus, our purpose was to review criti- of meningitis that could obviate inappro- cally those published cases of meningitis as- priate therapies, such as prolonged anti- sociated with the use of drugs. We have microbial therapy or high-dose steroids. compared the characteristics associated with The incidence of drug-induced men- the different drugs to see if differences ex- ingitis is unknown. Recent series have al- ist among them so as to suggest a specific lowed for an approximation to the extent drug as the culprit of the disorder and to of the problem. Four groups of drugs have distinguish it from other types of menin- gitides. From the Department of Neurology, Hospital Universitario Marque´s de Valdecilla, Using the MEDLINE database, we Santander, Spain (Dr Moris); and the Department of Neurology, Hospital de Galdacano, searched the literature up to June 1998 and Vizcaya, Spain (Dr Garcia-Monco). have included only those cases that speci- ARCH INTERN MED/ VOL 159, JUNE 14, 1999 1185 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 1. Drugs Involved in Drug-Induced Aseptic Meningitis* Drug No. of Drugs Involved %of Age, Mean ± SD Range of Latency Prior Exposure Group Reported Cases (No. of Cases) Females (Range), y (Median) to Drug, % NSAIDs 43 Ibuprofen1-31 (32) 67 37 ± 15 (21-73) 30 min to 4 mo (4 h) 45 Tolmetin32 (1) Sulindac33-38 (6) Naproxen39-41 (2) Diclofenac sodium42 (1) Ketoprofen41 (1) Antibiotics 39 Sulfamethizole43 (1) 78 44 ± 20 (6-82) 10 min to 10 d (3 h) 35 TMP-SMX44-61 (20) TMP62-67 (10) Isoniazid68 (1) Ciprofloxacin69 (1) Penicillin55 (1) Metronidazole70,71 (2) Cephalosporin72 (1) Pyrazinamide73 (1) Sulfisoxazole58 (1) IVIGs74-99 33 (0%-7%)† . 45 20 ± 17 (2-62) 10 h to 8 d (36 h) 35 OKT3100-119 39 (1%-7%, 5%)‡ . 57 37 ± 17 (7-62) 3 h to 7 d (72 h) 3 SLE group 22 Ibuprofen1-3,5,6,12-14,16,17,19,22,24,29 (14) 90 38 ± 14 (21-73) 20 min to 2 wk (4 h) 50 Tolmetin32 (1) Sulindac33 (1) Naproxen41 (1) Diclofenac sodium42 (1) TMP-SMX46,52 (2) TMP63 (1) Sulfisoxazole58 (1) *The systemic lupus erythematosus (SLE) group comprises all the patients with SLE irrespective of the offending drug. NSAIDs indicates nonsteroidal anti-inflammatory drugs; TMP-SMX, trimethoprim-sulfamethoxazole; TMP, trimethoprim; IVIGs, intravenous immunoglobulins; and OKT3, monoclonal antibodies against the T3 receptor. Ellipses indicate data not available. †Estimated prevalence from recent series.82,99 ‡Estimated prevalence from recent series.110,117 fied the cerebrospinal fluid (CSF) mental status (Table 2). This is also cannot be attributed to the drugs, findings and provided sufficient in- characteristic of infectious menin- since they also appear in up to 20% formation to exclude other causes. We gitis,121 and, therefore, the clinical of patients with bacterial meningitis only included cases that met the fol- presentation does not help in differ- irrespective of therapy.121 lowing criteria: a temporal relation- entiating DIAM from infectious The interval between drug in- ship with the drug intake, CSF pleo- meningitis. Other findings less fre- take and the development of men- cytosis (.5 cells/mm3) and negative quently reported included rash, ar- ingitis varies between several min- cultures, absence of any other expla- thralgias, myalgias, facial edema, and utes and 4 months for all patients in nationforthemeningitis,andthereso- lymph node or liver test abnormali- the drug groups and prior expo- lution of the syndrome on drug with- ties, which can also occur in infec- sure to the drug is present in 45% drawal. We discarded cases with nor- tious meningitis, mainly of viral ori- of patients taking NSAIDs; antibi- mal or absent CSF parameters (2 cases gin, with variable frequency. otics and IVIGs, 35%; and OKT3, 3% each by Sekul and colleagues82) as well There are statistically signifi- (Table 1). This rate of prior expo- as a case of pachymeningitis associ- cant differences in the presentation sure can be anticipated considering ated with penicillin therapy120 and 1 of the meningitides induced by the the high frequency with which caseofmyelopathyandbrainstemdys- different drugs, but these involve NSAIDs and antibiotics are pre- function with CSF pleocytosis after nonspecific symptoms that may be scribed and that IVIGs are usually trimethoprim-sulfamethoxazole ad- accounted for by differences in data used periodically to treat recurrent ministrationsuggestiveofsystemiclu- collection. For instance, patients in disorders such as idiopathic throm- puserythematosus(SLE)exacerbation the OKT3 monoclonal antibody bocytopenic purpura. On the con- (case 2).55 group had less vomiting and menin- trary, OKT3 antibodies are used for gismus and those in the antibiotic cases of transplant rejection, which CLINICAL CHARACTERISTICS group had more abnormalities of con- gives the patient little opportunity AND CSF PROFILES OF sciousness, but we do not believe that for prior exposure. There was no re- PATIENTS WITH DIAM these data differentiate or suggest a lation between the development of specific drug as the culprit. Overall, DIAM and the dose of the drug used, The vast majority of patients with seizures were recorded in 7% to 16% which was always within the rec- DIAM, irrespective of the offend- of the patients. Although it is well ommended therapeutic range. ing drug, presented with headache, known that some antibiotics can The CSF of patients with DIAM fever, meningismus, and changes in cause seizures,122 in this case they typically shows pleocytosis of sev- ARCH INTERN MED/ VOL 159, JUNE 14, 1999 1186 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 2. Clinical Signs and Symptoms of Patients With Drug-Induced Aseptic Meningitis* Patient Groups, %† NSAID Antibiotics IVIG OKT3 SLE‡ Total, % Fever 94 96 92 68 90 86 Headache 78 89 96 65 85 79 Meningeal signs 72 86 89 43 80 70 Nausea and/or vomiting 60 64 86 22 70 53 Rash 22 10 . 5 35 12 Abdominal pain 9 7 . 20 9 Arthromyalgias 22 21 . 19 30 54 Hypotension 19 3 . 3 30 9 Facial edema 25 21 . 20 24 Abnormal consciousness§ 50 64 23 59 50 50 Focal neurologic deficit 16\ 11¶ . 20# 10 18 Seizures 6 7 . 16 10 10 Papilledema 6 7 . 5 5 6 Lymphadenopathies 5 10 . 5 9 Abnormal liver 8 11 4 . 10 10 Photophobia . 34 32 10 32 *NSAIDs indicates nonsteroidal anti-inflammatory drugs; IVIGs, immunoglobulins; OKT3, monoclonal antibodies against the T3 receptor; and SLE, systemic lupus erythematosus. Ellipses indicate data not available. †See the following references for specific data about each patient group. NSAIDs, 1 to 42; Antibiotics, 43 to 73; IVIGs, 74 to 99; OKT3, 100 to 119, and SLE,1, 3, 5, 6, 12-14, 16, 17, 19, 22, 24, 29, 32, 33, 41, 42, 46, 58, 63, 64. ‡The SLE group includes all patients with SLE. §Includes somnolence coma and confusional states. \Includes dysarthria and right-gaze palsy (1 patient),21 left hemiparesis (1 patient),21 and bilateral Babinski sign (2 patients).17,36 ¶Includes dysphasia (1 patient),64 dysarthria and gait instability (1 patient),53 and bilateral hearing loss (1 patient).65 #Includes the following: 1 left abducens palsy and 1 bilateral abducens palsy,106,107 1 patient with brainstem reflexes abolition and bilateral Babinski sign,109 1 patient with hemiparesis,114 1 patient with ataxia, nystagmus, and decreased visual acuity,113 and 2 patients with hallucinations.111 Table 3.