The Challenge of Drug-Induced Aseptic Meningitis

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 meningitis (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 meningitis. 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 meningitides. 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-

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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 (Ͼ5 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-

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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. CSF Characteristics of Patients With Drug-Induced Aseptic Meningitis*

Cells/mm3, Predominant Cells, Median Glucose Value Median Protein Drug Group Median (Range) % of Patients (Range), mmol/L¶ Value (Range), g/L NSAIDs1-42 280 (8-5000) Lymphocytes, 24 3.16 (1.50-6.05) 1.24 (0.050-8.57) Neutrophils,† 73 Antibiotics43-73 147 (8-19 000) Lymphocytes, 24 3.39 (2.39-8.66) 1.20 (0.040-3.90) Neutrophils, 73‡ IVIGs74-99 651 (16-3500) Lymphocytes, 14 3.22 (1.05-4.44) 5.60 (0.15-4.50) Neutrophils, 78§ OKT3100-119 80 (8-3850) Lymphocytes, 37 4.00 (4.72-7.33) 6.60 (0.27-1.12) Neutrophils, 57 SLE1-3,5,6,12-14,16,17,19,22,24,29,32,33,41,42,46,58,63,64 331 (8-5000) Lymphocytes, 15 3.16 (1.50-6.05) 1.32 (0.50-8.97) Neutrophils, 80࿣

*CSF indicates cerebrospinal fluid; NSAIDs, nonsteroidal anti-inflammatory drugs; IVIGs, immunoglobulins; OKT3, monoclonal antibodies against the T3 receptor; and SLE, systemic lupus erythematosus. †In 2 cases, there were eosinophils representing 60% and 13% of the total cell count, respectively.8,41 ‡There were 2 cases with eosinophils representing 2% and 24% of the total cell count, respectively.49,61,69 §There were 4 cases with eosinophils representing 3%, 3%, 1%, and 100% of the total cell count, respectively.82,97 ࿣There was 1 case with eosinophils representing 13% of the total cell count.41 ¶To convert glucose value from milligrams per deciliter to millimoles per liter, multiply milligrams per deciliter by 0.055 51.

eral hundred to several thousand cells teristically, neutrophils predomi- spectively).82,97 The degree of pleo- per cubic millimeter, normal-to- nate, with a percentage more than cytosis correlated directly with the low glucose values, and increased the total cell count that varies be- severity of fever and inversely with protein values (Table 3). The num- tween an average of 57% in OKT3 the interval from drug exposure in ber of cells was significantly lower and 78% in IVIG. Eosinophils were a series of OKT3-associated DIAM, in the OKT3 group (P = .01, Kruskal- noted in 9 patients: 2 patients from but neither association reached sta- Wallis analysis of variance [ANOVA]) the NSAIDs group (between 13% tistical significance.110 than in the other 3 groups. The pro- and 60% of the total cell count),8,41 When performed, neuroimaging tein values were significantly lower 3 from the antibiotic group (2% and was normal in all patients except for in the IVIG and OKT3 groups com- 24%, respectively; no counts were 2 with NSAID-induced DIAM where pared with the other 2 groups (P = .01, given in the third case),51,61,69 and 4 diffuse contrast hemispheric enhance- Kruskal-Wallis ANOVA). Charac- in IVIG (1%, 3%, 3%, and 100%, re- ment was evident (by magnetic reso-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 4. Underlying Disorder in Patients With Drug-Induced Aseptic Meningitis*

Underlying Condition, No. (%) Drug Group, No. (%) Common Uncommon NSAIDs, 29 (67) SLE,1-3,5,6,12-14,16,17,19,22,24,29,32,33,41,42 18 (42) Undifferentiated connective tissue disease,21 1 (2) (N = 43) Mixed connective tissue disease,4,7,21,25,34,37 Isolated rheumatoid factor and antibodies to the SS-A antigen 6 (14) positivity of uncertain origin,18 1 (2) Isolated positive antinuclear antibodies of uncertain origin,8 1 (2) Ankylosing spondilitis,36 1 (2) Rheumatoid arthritis,30 1 (2) Antibiotics, SLE,46,52,58,63 4 (10) Sjo¨gren syndrome,62,63 2 (7) 14 (37) HIV infection,57,61,65 4 (10) Crohn disease,49 1 (2) (N = 38) Rheumatoid arthritis,48 1 (2) Interstitial cystitis,47 1 (2) Type 1 diabetes mellitus,59 1 (2) IVIGs, 29 (88) . . . Acquired immune neutropenia,88 1 (3) (N = 33) Positive antinuclear antibody titer and elevated glomerular basement membrane antibodies,95 1 (3) Idiopathic thrombocytopenic purpura,74,75,77-79,81,83-85,87,89-93,96,97 22 (65) Myasthenia gravis,80,86 2 (7) CIDP,76 1 (3) Polymiositis,82 1 (3) Muscular dystrophy,82 1 (3) Multifocal motor neuropathy with conduction blocks,82 1 (3) Paraproteinemic polyneuropathy,82 1 (3) Sensory neuropathy,98 1 (3)† Wegener granulomatosis,98 1 (3) OKT3, 37 (95) Kidney,100,102,105,106,108,109,111-115,118 19 (49)‡ Liver,101 3 (8) (N = 39) Heart,103,107,110,116,119 16 (40) Kidney and pancreas,104 1 (3)

*The different underlying conditions were arbitrarily split into common (Ͼ10% of cases) and uncommon (Ͻ10%). NSAIDs indicates nonsteroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus; HIV, human immunodeficiency virus; IVIGs, immunoglobulins; CIDP, chronic inflammatory demyelinating polyneuropathy; and OKT3, monoclonal antibodies against the T3 receptor. Ellipses indicate data not applicable. †The patient had SLE. ‡One of the patients had lupus nephropathy.

nance imaging [MRI] in one case and DIAM (Table 4). We pooled and analyzed their clinical and CSF char- by computed tomographic [CT] scan analyzed the clinical and CSF pro- acteristics (Table 5). In 8 pain the other), probably reflecting a files of this group of patients to see tients, meningitis was associated blood-brain barrier breakdown.24,37 In if they shared any special or distinc- with NSAIDs1-3,12,18,21,35,41 (18 epi- 2 additional patients with antibiotic- tive characteristic. The predomi- sodes), with antibiotics in 18 pa- related meningitis, MRI showed bilat- nance of females was marked (90%), tients43,45-50,55-57,62-65,72 (47 episodes), 115 eral supratentorial white matter T2- as expected for SLE, but there were with OKT3 in 1 (2 episodes), and signal abnormalities without gadolin- no other obvious indicators (Tables with IVIGs in 274,84 (4 episodes). The ium enhancement with complete 1, 2, and 4). highest number of episodes48 re- resolution in several months.58 Neu- Although migraine has been sug- ported in a single patient was 5, but roimaging was performed in 8 patients gested as a predisposing condition to we have only analyzed the first 3 epi- with OKT3-associated DIAM and was DIAM and reported in several sodes due to the low number of pa- abnormal in 3: a patient showed cere- patients,10,12,34,49,82,98 the retrospec- tients with more episodes and to the bral edema on brain CT scan109 and tive analysis of these heterogeneous lack of information on fourth and MRI disclosed high intensities on T2- case reports does not allow for the fifth episodes. Overall, there was a fe- weightedsequencesin2additionalpa- determination of the exact preva- male predominance (81%) with a tientsthatdisappearedin10days.113,114 lence of prior, potentially predis- mean age of 40 ± 22 years (range, The outcome was always ex- posing conditions such as migraine. 2-82 years). There was an underly- cellent provided that the offending To further complicate matters, the ing disorder in 18 (59%) patients, drug was withdrawn, with com- high prevalence of migraine in with SLE being the most frequent (8 plete recovery in all cases. In the case healthy populations (6%-12%)123 and patients),1-3,12,40,46,63 followed by Sjo¨- of OKT3, it resolved even without its even higher prevalence in popu- gren syndrome (2 patients),62,63 id- withdrawal in 45% of the patients. lations also prone to DIAM, such as iopathic thrombocytopenic pur- patients with SLE, should be con- pura (2 patients),74,84 rheumatoid UNDERLYING CONDITIONS IN sidered.124,125 arthritis (1 patient),48 human immu- PATIENTS WITH DIAM nodeficiency virus (2 patients),57,65 RECURRENT DIAM Crohn disease (1 patient),49 undif- Systemic lupus erythematosus stands ferentiated connective tissue dis- as the single most frequent under- We found 29 patients with recur- ease (1 patient),21 and positive rheu- lying condition associated with rent DIAM, totaling 71 episodes, and matoid factor and SS-A antigen (1

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 5. CSF Characteristics in Recurrent Episodes of Drug-Induced Aseptic Meningitis*

Cells/mm3, Median Glucose Median Median Time Latency Range Median Predominant Value (Range), Protein Value to Recovery Episode (Median) (Range) Cells, % mmol/L† (Range), g/L (Range), h First1-3,12,18,21,35,41,43,45-50,55-57,62-65,72,74,84,115 20 min to 4 mo 170 (8-1070) Lymphocytes, 15 3.16 (1.50-4.05) 0.88 (0.15-2.19) 72 (24-336) (n = 27) (18 h) Neutrophils, 85 Second1-3,12,18,21,35,41,43,45-50,55-57,62-65,72,74,84,115 20 min to 14 d 300 (10-5440) Lymphocytes, 24 3.28 (0.56-6.27) 1.22 (0.21-2.84) 48 (12-168) (n = 27) (2.5 h) Neutrophils, 76 Third35,41,45,48,49,55,56,62 2-14 d (15 h) 404 (20-2050) Lymphocytes, 14 3.44 (1.78-11.93) 1.45 (0.97-3.08) 48 (48-120) (n=8) Neutrophils, 86

*CSF indicates cerebrospinal fluid. †To convert glucose values from milligrams per deciliter to millimoles per liter, multiply milligrams per deciliter by 0.055 51.

patient).18 Cerebrospinal fluid analy- antibiotics (Table 1). In cases where sidering the difficulty of making a de- sis of these episodes revealed a poly- bacterial meningitis is a possibility, finitive diagnosis in viral infections. morphonuclear pleocytosis that we suggest the patient be treated Polymerase chain reaction could have tended (did not reach statistical sig- with third-generation cephalospor- been of help in elucidating a pos- nificance) to be more pronounced ins, which are known to cause DIAM sible viral origin,129 but this informa- with subsequent episodes. A signifi- only exceptionally72 and that would tion was not available in any of the cant increase in protein content dur- be active against the most frequent reported cases, since most of them ing the second and third episodes in organisms in a healthy individual predate the use of polymerase chain relation to the first one (P = .005, until the appropriate CSF studies are reaction. In any case, the time to re- Kruskal-Wallis ANOVA) was also available. Although corticosteroids covery after drug withdrawal may be noted. There was no change in the have been used in several patients, of help, since it is rapid in DIAM (1-5 differential cell count or in the glu- their effectiveness in DIAM has not days) but usually takes 10 to 14 days cose contents. The latency from ex- been proven and therefore cannot be in viral meningitis. posure to the drug and the recovery recommended routinely. Many other noninfectious rate was also similar among the dif- Since recovery on drug discon- causes of aseptic meningitis exist, an ferent episodes. tinuation is the rule, chronic infec- important fact considering that many tious meningitis (tuberculous, fun- patients with DIAM harbor under- DIFFERENTIAL DIAGNOSIS gal, etc) would only rarely pose a lying systemic disorders that may diagnostic problem. If such is the cause meningitis and that can also The differential diagnosis of DIAM is case, appropriate CSF studies (cul- predispose them to neurologic in- broad and includes infectious causes. ture in appropriate media and ad- fections by diverse organisms. In the A meningeal syndrome accompa- equate stains) will be necessary. Men- setting of SLE, DIAM needs to be nied by CSF neutrophilic pleocyto- ingitis due to parasites may need to specifically distinguished from lu- sis suggests acute bacterial meningi- be ruled out in those cases with CSF pus aseptic meningitis. Although tis, which needs to be ruled out by eosinophilia that occur in the appro- signs of meningeal inflammation are CSF culture. More than 85% of the priate epidemiological context. present at autopsy in 18% of pa- patientswithbacterialmeningitispres- Viral aseptic meningitis is an- tients with SLE,130 aseptic meningi- ent with fever, headache, meningis- other important consideration in tis is infrequently diagnosed, since mus, and signs of cerebral dysfunc- terms of frequency, although less the clinical presentation can be over- tion (ie, confusion, delirium, or a critical in terms of prognosis and whelmed by other neuropsychiat- declining level of consciousness rang- management. Clinically, it is marked ric manifestations. Unlike DIAM, the ing from lethargy to coma).126,127 by fever (76%-100%), nuchal rigid- cellular infiltrate of the CSF in lu- Therefore, distinction on clinical ity, and headache that may be ac- pus meningitis is usually lympho- grounds alone is not possible. companied by vomiting, rash, diar- cytic (Ͻ50 cells) and is accompa- Even more problematic is the rhea, pharyngitis, arthralgias, and nied by other data consistent with case of a patient treated with an an- myalgias.128 Neutrophils may occa- a lupus flare-up.131,132 In turn, DIAM tibiotic who develops meningitis and sionally dominate the CSF profile could mimic a drug-induced exac- in whom the possibility of a par- early in the infection, although there erbation in SLE if accompanied by tially treated meningitis should be is usually a shift to lymphocytic pre- systemic manifestations. The rapid considered first but needs to be sepa- dominance during the first 48 hours. onset and resolution of the signs and rated from an antibiotic-related Cerebrospinal fluid glucose levels are symptoms as well as the lack of data DIAM. Again, these entities cannot usually normal. Again, clinical and of SLE activity, especially a fall in se- be distinguished on clinical and CSF CSF overlapping with DIAM may oc- rum complement levels, argue grounds alone. Of help may be to cur. It could also be argued whether against an exacerbation of SLE.1 consider the type of antibiotic, since certain cases of DIAM would in fact Antibiotics are probably under- DIAM is mainly caused by certain correspond to viral meningitis con- recognized as etiologic agents of

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 meningitis and must be considered NSAID-INDUCED MENINGITIS Some authors1,4,17,20 have pro- also in the differential diagnosis of posed a role for immune com- recurrent meningitis, particularly in In the case of NSAIDs, it seems clear plexes, but controversial findings relation to anatomical skull de- that inhibition of the cyclooxygen- have been reported. Chez and col- fects, parameningeal infectious foci, ase pathway is not involved. It has leagues20 found an 8.75-fold in- immunodeficiencies, and Mollaret been reported that patients can tol- crease in CSF-immune complexes meningitis.45 erate other NSAIDs both before and over the normal serum values in a The abrupt onset in some pa- after the meningitis episode and that healthy patient with ibuprofen- tients with DIAM may suggest intra- not all the drugs in this group lead induced meningitis. They and oth- cranial bleeding, especially in patients to meningitis.3-7,13,25,33,37 Cerebrospi- ers17 have also found evidence of in- with idiopathic thrombocytopenic nal fluid penetration does not seem trathecal IgG production. However, purpura and low platelet counts. relevant since it is similar for all the serum immune complex levels were Computed tomographic scans can be NSAIDs.135 Some data point to a hy- found to be normal in another study1 used to rule out hemorrhage.91 persensitivity reaction: the tempo- and high in another.4 Based on these Cerebrospinal fluid pleocyto- ral relationship between drug in- findings, some authors have con- sis133 may occasionally accompany take and the development of cluded that ibuprofen-induced men- migraine, but the cell count is al- meningitis; prior exposure to the of- ingitis is an antigen-specific hu- most always lymphocytic and rarely fensive drug and disappearance of moral immune process confined to exceeds 100 cells/mm3. Since NSAIDs symptoms after drug discontinua- the central nervous system, where are commonly used to treat migraines tion; the presence of accompany- the drug, and not a metabolite, and can lead to DIAM, these drugs ing “allergic” signs, such as facial would potentiate the activity of a could play a role in producing pleo- edema and conjunctivitis (NSAIDs preexisting autoantibody, result- cytosis, but this aspect has never 25%, antibiotics 21%) and rash ing in complement fixation and de- been assessed systematically. Some (NSAIDs 22%, antibiotics 10%); and velopment of an acute meningi- patients develop the “pseudomi- more severe symptoms on drug re- tis.20 graine with pleocytosis” syndrome, exposure. Latency after drug in- Bernstein4 has proposed that which is characterized by variable take, however, was not shorter with the drug combines with a CSF or neurologic deficits, headache, fe- reexposure. In those patients who meningeal protein that acts as a hap- ver, and lymphocytic pleocyto- developed meningitis on their first ten, leading to an inflammatory re- sis.134 The predominance of lympho- exposure to the NSAIDs, it has been sponse in the meninges. However, cytic pleocytosis in the CSF and the suggested that a prior contact with ibuprofen does not reach high con- concomitant focal neurologic defi- a chemical cross-reactive with the of- centrations in the CSF, even with cit (present in 86% of patients with fending drug could have mediated high serum concentrations, which pseudomigraine but only in 10%- the sensitization.33 A few patients indicates that DIAM is not due to ac- 16% of DIAM) might be of help to have developed meningitis after the cumulation of antigenic determi- differentiate this entity from DIAM. intake of several unrelated drugs, nants of the drug in the CSF. As for migraine, the hypothetical role which could suggest an individual Two authors8,41 reported eo- of drugs, such as NSAIDs, should be predisposition,32,53 although CSF sinophilic pleocytosis in the CSF of assessed in pseudomigraine with data that confirm the meningitis are patients with ibuprofen-induced pleocytosis. The only confirmatory lacking or incomplete. meningitis without concomitant eo- test of DIAM would be a rechal- In SLE-susceptible mice (NZB sinophilia, which suggests a pro- lenge with the drug, which has been and NZW), meningitis developed cess confined to the meningeal com- previously reported in the litera- and was more intense in older ani- partment. ture but does not seem ethically jus- mals that had been exposed to ibu- Taken together, the available tified.1,12,49 profen longer. The mice developed data suggest that NSAID-related meningitis (100% of the animals), meningitis develops in individuals PATHOGENESIS only if exposed to ibuprofen and not rendered susceptible by an under- to ketoprofen (another propionic lying autoimmune disorder who The pathogenic mechanisms of acid derivative), suggesting that only were previously sensitized or had a DIAM are not fully understood, but certain drugs lead to meningitis.136 natural immunity to the drug. Why there is evidence to suggest that they Furthermore, a specific cell-medi- the reaction is confined to the me- may be diverse, perhaps different for ated immunity to ibuprofen has ninges is obscure but might in- the various types of drugs. Most of been described in patients with volve cross-reactive mechanisms the authors invoke a hypersensitiv- SLE who had not been previously with antigenic determinants of the ity mechanism (especially type 1 and exposed to this drug, perhaps due central nervous system. 3) for NSAID-, IVIG- and antibiotic- to cross-reactivity with some natu- related cases. OKT3 cases are likely ral constituents to which the auto- ANTIBIOTIC-INDUCED mediated, at least in part, by cyto- immune reaction is directed.137 MENINGITIS kine release. However, it is striking Also, presumably a lack of sup- that such reactions are mainly or ex- pressor cells as noted in SLE, could The mechanism of action of antibi- clusively confined to the CSF com- allow for a greater magnitude of otic-induced meningitis is also sup- partment. responsiveness.138 posed to be due to a hypersensitiv-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 ity reaction for the same reasons IgG. It was increased in all the pa- with Sjo¨gren syndrome and trigemi- described for NSAIDs. Unlike tients in whom it was measured, al- nal neuralgia, 2 with manic depres- NSAIDs, immune complexes have though IgG indexes did not reveal sive syndrome and another with iso- been detected in the serum of 3 pa- intrathecal synthesis.82 Shorr and lated trigeminal neuralgia.148-151 The tients with meningitis induced by tri- Kester95 also found increased levels clinical case was indistinguishable methroprim-sulfamethoxazole– of CSF IgG (1130 g/L, 28% of the to- from other DIAM, although 1 pa- induced meningitis, but these were tal CSF protein). Serum immuno- tient had myoclonus with normal not found in their CSF.48,62 In a case globulins, especially IgG, can enter carbamazepine levels.149 There was of cephalosporin-related DIAM,72 the CSF mainly if there is a blood- peripheral eosinophilia (30% of to- immune complexes were present brain (or blood-nerve) barrier break- tal white blood cell count) in 2 of both in serum and CSF as well as down. Since the infused IgG, de- them 148,150 and 2% eosinophils in the an increased IgG value in the CSF. rived from a pool of more than 5000 CSF in 1.150 This may suggest either that trans- donors, is allogenic, it could inter- As noted by Quinn and col- fer of immune complexes to the act with antigenic determinants on leagues,8 counting CSF eosinophils CSF is not involved in the patho- the endothelial cells of the menin- is challenging because of technical genesis of the illness or that they geal vasculature, resulting in a cy- difficulties, inexperience of the ex- are not accesible for assay. Joffe and tokine-mediated inflammatory re- aminer, and the fragility of this cell. coworkers48suggest that immune action.82 It is thus likely that the presence of complexes consisting in part of eosinophils in the CSF is underre- trimethroprim-sulfamethoxazole OKT3 ANTIBODY-INDUCED ported. may have a predilection for deposi- MENINGITIS Merrin and Williams152 re- tion in the choroid plexus, induc- ported a case of aseptic meningitis ing a necrotizing small-vessel vas- Most authors believe that T cells are in a 37-year-old woman with Sjo¨- culitis and leading to an aseptic opsonized by OKT3 in the pres- gren syndrome and polyarthritis, 3 meningitis.48 Gordon and col- ence of complement and are phago- weeks after starting sulfasalazine and leagues49 found high levels of im- cytized by the reticuloendothelial 8 hours after subsequent rechal- mune complexes in the CSF, sug- system, resulting in the release of cir- lenge with 0.5 g of the drug. An- gestive of an intrathecal immune culating mediators, which induce in- other case of aseptic meningitis in- response. This patient was rechal- flammation in the meninges110,113,143 duced by sulfasalazine has been lenged and the level of CSF trime- and fluid leakage leading to brain reported in a 41-year-old man with throprim-sulfamethoxazole was be- swelling.109 These cytokines in- rheumatoid arthritis.153 low the therapeutic range, excluding clude tumor necrosis factor, inter- We found 3 cases of isolated also a meningeal toxic effect.49 An leukin 2, and interleukin 6.114 More- DIAM associated with phenazopyri- underlying defect involving the me- over, administration of OKT3 dine hydrochloride,154 zimeldine hy- ninges has also been proposed and antibodies increases systemic cyto- drochloride (a serotonin uptake in- also that certain drugs may “trig- kine levels, which may contribute to hibitor unavailable since 1983),155 ger” a reaction leading to clinical the inflammatory response.144 It has and cytarabine hydrochloride.156 In meningitis.139,140 been suggested that prior adminis- the latter, meningitis was associ- tration of antihuman tumor necro- ated with cerebellar dysfunction. IMMUNOGLOBULIN-INDUCED sis factor–monoclonal antibodies Sergent and colleagues157 de- MENINGITIS could prevent the systemic syn- scribed 2 patients with SLE who de- drome (DIAM is not mentioned), al- veloped a meningeal reaction after The possibility that this type of though it has not yet been proven.145 azathioprine therapy, but both pa- DIAM is caused by sensitivity to the Other mechanisms implicate tients had clinical and laboratory evi- stabilizing agents of the commer- certain surface antigens that are com- dence of active SLE and they also had cial preparations, such as polyeth- mon to both circulating lympho- meningitis not associated with the ylene glycol, maltose, sucrose, or gly- cytes and to cells in the central ner- administration of the offending drug. cine, seems unlikely since this vous system.146,147 The OKT3 Also, single case reports of syndrome developed in the same pa- monoclonal antibodies might bind DIAM in relation with salicylate tients who received other prior im- to these cross-reacting neural anti- overdose,158 hepatitis B vaccina- munoglobulin preparations,74,141 and gens inciting local inflammation. tion,159 and ranitidine intake160 have there are at least 6 different com- This would likely implicate that been published. mercial products that induced asep- OKT3 antibodies cross the blood- In conclusion, the possibility of tic meningitis.142 brain barrier, a phenomenon dis- DIAM should be considered in ev- Considering the presence of eo- puted by some authors.110 ery patient with neutrophilic men- sinophils in the CSF of some pa- ingitis and negative CSF culture, es- tients, Sekul et al82 have suggested OTHER AGENTS ASSOCIATED pecially in the presence of an a hypersensitivity reaction caused by WITH DIAM underlying autoimmune disorder. the direct entry of the immuno- Most commonly, NSAIDs, antibiot- globulins into the cerebrospinal Four patients have been described ics, IVIGs, and OKT3 monoclonal compartment. They also propose an who developed meningitis after car- antibodies are the causative drugs, alternative mechanism involving bamazepine therapy, one of them acting through different and par-

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