Neuropharmacology & Neurotherapeutics

Updated 08.17.2022
Released 06.30.1998
Expires For CME 08.17.2025

Drug-induced aseptic meningitis

Author: Douglas J Lanska MD FAAN MS MSPH

Introduction

Overview

Several classes of drugs have been reported to cause drug-induced aseptic meningitis, particularly nonsteroidal anti-inflammatory drugs, antimicrobials, corticosteroids, and antineoplastic drugs. Drugs and diagnostic agents administered intraventricularly and intrathecally can cause aseptic meningitis. This article examines the pathogenesis, differential diagnosis, and management of this condition.

Key points

	• Drug-induced aseptic meningitis is difficult to distinguish from other causes of aseptic meningitis.
	• CSF proteins are usually elevated.
	• CSF culture results are always negative.
	• Although several drugs are known cause aseptic meningitis, the incidence appears to be the highest for nonsteroidal anti-inflammatory drugs and drugs introduced intrathecally.
	• Management involves discontinuation of the offending drug.

Historical note and terminology

Meningism is the triad of nuchal rigidity, photophobia, and headache and is a sign of irritation of the meninges, as seen in meningitis, subarachnoid hemorrhages, and aseptic meningitis. Meningismus is meningism in the absence of meningitis. Meningismus is often associated with acute febrile illness, especially in children and adolescents. Meningismus is frequently seen with upper lobe pneumonias, particularly right upper lobe pneumonias (67; 140; 139; 149).

Although viral infection is the usual cause of aseptic meningitis, chemical agents, such as drugs, may produce the same clinical syndrome. Swedish pediatrician Arvid Wallgren (1889–1973) first proposed the following diagnostic criteria for aseptic meningitis in 1925 (194):

• Acute onset of signs and symptoms of meningeal involvement (eg, headache, fever, and stiff neck)
• Changes in CSF suggestive of meningitis (eg, pleocytosis)
• Absence of bacteria in CSF as demonstrated by culture
• Short and benign course, with typical recovery within days
• Absence of local parameningeal infection (eg, otitis media, epidural abscess)
• Absence of epidemic meningitis in the community

Postoperative aseptic meningitis was first described in 1928 by American neurosurgeon Harvey Cushing (1869–1939) and Cushing's assistant at the time, Percival Bailey (1892–1973) (35).

Mollaret meningitis, described by French neurologist Pierre Mollaret (1898–1987) in 1944, is a recurrent form of aseptic meningitis of unclear etiology (122). Bruyn and colleagues proposed the following criteria for Mollaret meningitis in 1962 (22; 61):

	• Recurrent episodes of meningism and fever
	• Attacks separated by symptom-free periods of weeks to months
	• CSF pleocytosis of mixed type with large "endothelial" cells, neutrophils, and lymphocytes during attacks
	• Spontaneous remission of symptoms and signs
	• No causative organism identified

In some cases of Mollaret meningitis, no organism was identified despite extensive investigation (63; 117; 95; 28; 164). Some cases had presumptive noninfectious causes, such as systemic lupus erythematosus (117). In one case of so-called Mollaret meningitis, two of the five attacks were drug induced (179). However, many cases of so-called Mollaret meningitis have been linked to herpes simplex virus type II (HSV-2) (12; 52; 101; 115; 168; 01; 75; 150; 188; 202; 66; 68), which then requires that either the criteria be modified (with elimination of the criterion that no causative agent has been identified) or that those cases be labeled as recurrent aseptic meningitis due to a specific agent.

Because Mollaret meningitis is a recurrent, benign (non-cancerous), aseptic meningitis, it is also referred to as benign recurrent lymphocytic meningitis. However, all cases of recurrent lymphocytic meningitis are benign in the sense that they are non-cancerous, so the word "benign" is redundant and, therefore, not needed to modify "recurrent lymphocytic meningitis." Because of these definitional difficulties, some have suggested restricting the term "Mollaret meningitis" to idiopathic recurrent aseptic meningitis (142), although the eponym can probably be abandoned for all cases of recurrent aseptic meningitis. It would be much clearer to state, for example, idiopathic recurrent aseptic meningitis or recurrent lymphocytic meningitis due to HSV-2, etc.

Before the term "aseptic meningitis" was introduced, the term "hypersensitivity meningitis" was used in the literature to describe the meningeal reaction accompanying serum sickness and allergic reactions in a patient following the first dose of the second course of sulfathiazole (106). Some of these cases fulfill the present criteria of drug-induced aseptic meningitis. Two patients experienced headache, stiff neck, and fever following administration of sulfanilamide and later developed encephalomyelitis (59). A patient receiving sulfamethoxazole developed aseptic meningitis that recurred with rechallenge after the patient had recovered from the initial exposure (15).

Clinical manifestations

Presentation and course

• The initial presentation, eg, headache and neck stiffness, is like meningitis due to other causes and signs of reaction to a drug that may appear later.

The classical manifestations of meningitis--headache, nuchal rigidity, and fever (or, collectively, "meningism")--are also features of aseptic meningitis. Other symptoms may include photophobia, myalgia, nausea, vomiting, myalgias, and confusion.

If aseptic meningitis is part of a neurotoxic reaction to a drug, there may be additional manifestations other than meningitis.

Prognosis and complications

Prognosis varies with the age of the patient as well as the cause of meningitis. Viral meningitis is usually a benign condition. All drug-induced aseptic meningitis cases reported in the literature resolved without mention of specific neurologic complications. However, there is some concern regarding long-term neuropsychiatric sequelae. Some studies have reported decreased psychomotor speed and impaired executive as well as visuo-constructive functions following aseptic meningitis (37).

Clinical vignette

A 35-year-old man with a history of systemic lupus erythematosus was admitted to the hospital with chills, headache, and nausea 30 minutes after ingesting a 400 mg tablet of ibuprofen. He had a temperature of 38.5°C and a stiff neck, but no neurologic deficit. A lumbar puncture showed an opening pressure of 210 mm of water, with CSF protein of 120 mg/dL (normal typically < 45 mg/dL) and white blood cell count of 1120/µL, of which 98% were polymorphonuclear. The peripheral leukocyte count was 16,000/µL. A tentative diagnosis of meningitis was made, and the patient was treated with antibiotics. During the next 24 hours, his symptoms resolved. All cultures of blood and CSF were negative for microorganisms. A few months earlier, the patient had had a similar but less severe episode following ingestion of ibuprofen, from which he recovered spontaneously without being hospitalized and without having the matter investigated. A diagnosis of ibuprofen-induced aseptic meningitis was made, and the patient was advised to avoid taking ibuprofen.

Biological basis

• Proposed pathogenetic mechanisms of drug-induced aseptic meningitis fall include (1) hypersensitivity reactions and (2) direct irritation of the meninges, with direct instillation of an agent into the subarachnoid space.

• Support for a hypersensitivity mechanism includes (1) the development of drug-induced aseptic meningitis after repeat exposure; (2) the rapid development of symptoms after an inciting exposure; (3) the progressively shorter onset periods with repeated exposures; (4) the associated development of classic features of hypersensitivity reactions (eg, facial edema, conjunctivitis, pruritus); and (5) elevated levels of immune complexes in the CSF of affected patients.

Pathogenesis of drug-induced aseptic meningitis

Proposed pathogenetic mechanisms of drug-induced aseptic meningitis fall include (1) hypersensitivity reactions and (2) direct irritation of the meninges with direct instillation of an agent into the subarachnoid space (205).

Diagnosis of immunologic hypersensitivity reactions is often challenging. Clinical symptoms develop soon after systemic administration of the responsible drug, usually within a week, although the time to symptom onset can be shortened to a few hours in cases of drug rechallenge (whether intentional or inadvertent) (205). Support for a hypersensitivity mechanism includes (1) the development of drug-induced aseptic meningitis after repeat exposure; (2) the rapid development of symptoms after an inciting exposure; (3) the progressively shorter onset periods with repeated exposures; (4) the associated development of classic features of hypersensitivity reactions (eg, facial edema, conjunctivitis, pruritus); and (5) elevated levels of immune complexes in the CSF of affected patients. Inciting drugs may behave as haptens that bind to proteins, prompting the immune system to subsequently recognize those proteins as foreign antigens.

Unlike the hypersensitivity reactions, drug-induced aseptic meningitis due to direct irritation is usually easily recognized, although the onset of symptoms may be delayed up to several weeks following drug administration. The toxicity of the drug or the chemical in the CSF depends on the following factors:

• Concentration of the drug or the chemical
• Lipid solubility
• Particle size
• Ability to ionize in the CSF
• Duration of contact with CSF

Some patients with comorbid conditions may be at an increased risk of drug-induced aseptic meningitis, including those with autoimmune disorders, rheumatologic disorders, and AIDS.

Drug-induced aseptic meningitis has been reported as an adverse reaction to multiple drugs and chemicals (Table 1).

Table 1. Selected Drugs, Chemicals, and Devices Associated with Drug-Induced Aseptic Meningitis

Antiepileptic drugs
	• Carbamazepine • Lamotrigine*
Antimicrobial drugs*
	• Antimicrosporidial
		- fumagillin
	• Antivirals
		- valacyclovir
	• Cephalosporin • Fluoroquinolones
		- ciprofloxacin - moxifloxacin
	• Isoniazid • 5-Nitroimidazole derivatives
		- metronidazole - ornidazole
	• Penicillin and its analogs
		- amoxicillin*
	• Pyrazinamide • Rifampin • Sulfonamides
		- trimethoprim* - trimethoprim/sulfamethoxazole* - sulfasalazine
Antineoplastics (systemic use)
	• Cytosine arabinoside
Histamine-2 blockers
	• Famotidine • Ranitidine
Immunosuppressive drugs
	• Azathioprine • Corticosteroids
		- Hydrocortisone sodium succinate - Methylprednisolone acetate
	• Leflunomide
Monoclonal antibodies*
	• Adalimumab • Cetuximab • Efalizumab • Infliximab • Muromonab CD-3* • Natalizumab • Trastuzumab
Nonsteroidal antiinflammatory drugs*
	• Celecoxib • Diclofenac • Ibuprofen* • Ketoprofen • Loxoprofen • Naproxen (198) • Piroxicam • Rofecoxib (withdrawn from U.S. and other markets in 2004 due to adverse effects) • Salicylates • Sulindac • Tolmetin (161)
Vaccines
	• Hepatitis B • Measles, mumps, and rubella* (only some vaccine formulations) • Mumps* (only some vaccine formulations) • Poliomyelitis
Intrathecal and intraventricular drugs
	• Antimicrobials
		- Gentamicin
	• Antineoplastics
		- cytosine arabinoside - methotrexate
	• Baclofen • Bupivacaine (spinal anesthesia) (47) • Corticosteroids • Hydromorphone (201) • Monoclonal antibodies
		- Trastuzumab
Intrathecal diagnostic agents
	• Radiolabeled albumin • Radiologic contrast media
		- iophendylate - metrizamide - iohexol
Miscellaneous
	• Allopurinol (xanthine oxidase inhibitor, urate-lowering medication) (50; 72; 08) • Intravenous immune globulin* • Isotretinoin (vitamin A derivative) (25)
Devices used in the management of neurologic disorders
	• Coils used for treatment of intracranial aneurysms • Devices implanted into the brain • Intraventricular catheters
* Denotes well documented. These categories (and selected others) are further discussed in this section.

A systematic literature review found that nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, intravenous immunoglobulins, and OKT3 antibodies [monoclonal antibodies against the CD3(T3) receptor] are the most frequently reported causes of drug-induced aseptic meningitis (125). Such cases often present diagnostic and therapeutic challenges because resolution occurs several days after drug discontinuation. The clinical and cerebrospinal fluid profile of a neutrophilic pleocytosis does not allow drug-induced aseptic meningitis to be distinguished from infectious meningitis, and no specific diagnostically useful characteristics have been linked with specific drugs (125).

In a report from the French Pharmacovigilance Database, the most frequently implicated drugs in cases of drug-induced aseptic meningitis were intravenous polyvalent immunoglobulin, nonsteroidal anti-inflammatory drugs, vaccines, and antimicrobials (19).

Antiepileptic drugs

Lamotrigine. Lamotrigine has been implicated as a cause of drug-induced aseptic meningitis (71; 171). In 15 of 40 cases (38%) of drug-induced aseptic meningitis due to lamotrigine, a positive rechallenge was documented; the median time to onset of symptoms on rechallenge was only 60 minutes (171).

Carbamazepine. Carbamazepine has also been implicated as a cause of drug-induced aseptic meningitis (78; 172; 76; 38; 91).

Antineoplastics

Drug-induced aseptic meningitis has been reported after systemic treatment with cytosine arabinoside (169; 180; 26; 143; 187; 191; 104). Drug-induced aseptic meningitis associated with antineoplastic therapy may be difficult to distinguish from neoplastic meningitis.

Antibiotics

Trimethoprim-sulfamethoxazole. Drug-induced aseptic meningitis is a recognized adverse effect of trimethoprim-sulfamethoxazole (TMP-SMX) or trimethoprim-containing drugs (183; 55; 155; 195; 87; 03; 53; 186), and TMP-SMX is the most common antibiotic to cause drug-induced aseptic meningitis (21). The most current use of TMP-SMX is limited to Pneumocystis carinii pneumonia prophylaxis in AIDS patients.

According to a review of 41 cases in the literature up to 2014, there is a predominance of female patients and patients with autoimmune disease (21). Fever, headache, neck pain, and altered mental status are the most common clinical manifestations, whereas severe reactions include seizures and alterations of consciousness, including coma. Typical CSF findings include elevated white blood cell count with neutrophil predominance, elevated protein, and normal glucose. Symptoms remit over 48 to 72 hours after withdrawal of TMP-SMX. Full recovery is typical after discontinuation of the drug, but persistent paraplegia has been reported in one case. Affected individuals subsequently react to TMP and SMX alone and, therefore, should be advised to avoid both classes of medication after diagnosis. The mechanism is unknown, although an IgE-mediated allergic reaction is unlikely. Interleukin-6 has been implicated as a key mediator in trimethoprim-associated drug-induced aseptic meningitis, and a rise in the level of this inflammatory cytokine in the blood and CSF is a potential biomarker of trimethoprim-associated drug-induced aseptic meningitis (06; 07).

Colistin. Colistin, an antibiotic that penetrates the brain poorly, has been used via intrathecal and intraventricular administration for CNS infections due to multidrug-resistant Acinetobacter baumannii. Colistin is an effective treatment in this situation but may cause chemical meningitis or ventriculitis, as it did in 3 of 24 cases (13%) in one series (97).

Other. Drug-induced aseptic meningitis has been reported with multiple other systemic antibiotics, including cephalosporins (33; 132), fluoroquinolones (159), penicillin (155), amoxicillin (167; 151; 05; 29; 174), rifampin (182), and fumagillin (11).

Monoclonal antibodies

Cetuximab. Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor and is used for the treatment of cancer. There are isolated case reports of drug-induced aseptic meningitis with cetuximab (131; 54; 184). The symptoms—headache, neck stiffness, and high fever—develop within a few hours of the first cetuximab administration. Diagnosis is established by CSF analysis. Recovery usually occurs within days to weeks after withdrawal of the drug.

Muromonoab-CD3. Muromonoab-CD3 (Orthoclone OKT3), a monoclonal murine IgG immunoglobulin directed at CD3 receptors of the surface of T-lymphocyte, is used to reduce acute rejection in patients with organ transplants. Muromonab-CD3 was approved by the U.S. Food and Drug Administration in 1986 for the treatment of glucocorticoid-resistant rejection of allogeneic renal, heart, and liver transplants.

The binding of muromonab-CD3 to CD3 receptors can stimulate T cells to release cytokines like tumor necrosis factor and interferon gamma, especially during the first infusion. This cytokine release syndrome includes a range of unpleasant but relatively minor side effects (eg, fever, chills, rigors, myalgia, headaches, nausea, diarrhea, fatigue, skin reactions, hypotension) and potentially life-threatening conditions (eg, apnea, flash pulmonary edema, and cardiac arrest). To minimize the risk of cytokine release syndrome, glucocorticoids (eg, methylprednisolone), acetaminophen, and diphenhydramine are given before the infusion. Neurologic side effects include aseptic meningitis, cerebritis, encephalopathy, and lateralizing seizures (112; 177; 73; 154; 156; 02; 24; 120; 111; 175; 200; 125), and many reports have considered these part of the cytokine release syndrome (43). Other adverse effects include leucopenia and severe infections.

Others. Additional reports of drug-induced aseptic meningitis with monoclonal antibodies have included adalimumab (84; 196), infliximab (90), ipilimumab (193), natalizumab (60), and intrathecal trastuzumab (62).

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) has been employed in the treatment of various medical conditions, such as Guillain-Barré syndrome, dermatomyositis, idiopathic thrombocytopenic purpura, and Kawasaki disease. Multiple cases of drug-induced aseptic meningitis have been attributed to IVIG (166; 203; 128; 18; 189; 99).

A retrospective review at a large tertiary care center from 2008 to 2013 identified eight cases of IVIG-associated drug-induced aseptic meningitis from among 1324 unique patients who received a total of 11,907 IVIG infusions (554,566 g) for various conditions (18). Eight cases of aseptic meningitis were identified, suggesting an overall drug-induced aseptic meningitis incidence of 0.60% for all patients and 0.067% for all IVIG infusions. Symptoms manifested within 24 to 48 hours of infusion. The reactions were self-limited and resolved within 5 to 7 days of stopping IVIG.

The pathogenetic mechanisms of drug-induced aseptic meningitis due to IVIG are not well understood. Because serum immunoglobulins, particularly IgG, can cross the blood-brain barrier, it is possible that IVIG (obtained from a pool of multiple donors) can produce a hypersensitivity reaction limited to the leptomeninges. Alternatively, IVIG may react with antigenic determinants within or in contact with the CSF (eg, on the endothelial cells of meningeal blood vessels), producing a release of cytokines and an inflammatory reaction.

A history of migraine appears to increase the risk of drug-induced aseptic meningitis in patients receiving IVIG (166), as do higher rates of infusion, larger doses administered, and inadequate patient hydration.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Multiple NSAIDs have been implicated in causing drug-induced aseptic meningitis, a reaction that appears unrelated to the chemical class of NSAIDs. In NSAID drug-induced aseptic meningitis, meningitis mostly occurs within weeks of starting therapy, but cases have been reported as late as 2 years after initiation of therapy. Cross-reactivity of the NSAIDs is not a general feature because, with a few exceptions (09), patients who develop aseptic meningitis after exposure to one NSAID have been previously and subsequently treated with other NSAIDs, without any reaction. Systemic lupus erythematosus seems to predispose to NSAID-related drug-induced aseptic meningitis (125). Immune abnormalities (eg, serum and CSF anti-ribonucleoprotein antibodies) may impact the development of NSAID drug-induced aseptic meningitis in patients with a history of connective tissue disorders (114).

Ibuprofen. Of the NSAIDs, ibuprofen has been most frequently implicated in drug-induced aseptic meningitis (102; 110; 116; 30; 74; 103; 135; 146; 157; 123; 94; 133; 42; 147; 127). Affected individuals may have repeated episodes with even small doses of ibuprofen (51). Patients with systemic lupus erythematosus are at an increased risk of NSAID-induced aseptic meningitis, and the meningitis may be a specific cell-mediated immune response (124; Mousavi Mirzae and Ahmadi 2021). Indeed, the most common background disease among these patients is systemic lupus erythematosus (173; 197; 199; 162; 170; 160; 181; 86; 65; 32; 77; 126; 58), but cases have also been reported in patients with mixed connective tissue disease (79; 94) and rheumatoid arthritis (81), for example, and in patients without connective tissue diseases (116).

Vaccines

Monovalent vaccines for mumps and MMR. All commercially available mumps vaccines contain live attenuated virus. Mumps vaccines may be monovalent but are usually given in combination with measles and rubella vaccines (MMR). More than 10 mumps vaccine strains have been used in different countries. Vaccines made with some of these strains and with various processing methods were linked to outbreaks of aseptic meningitis.

In general, no significant increased risk of aseptic meningitis has been observed with the Jeryl Lynn or Rubini strains, or the RIT 4385 mumps strain (used in Priorix), which is derived from the Jeryl Lynn mumps strain. Significantly increased risks have been observed for the Urabe, Hoshino, and Leningrad-Zagreb strains (153; 89; 49; 36; 163; 98; 20; 144; 145). Because of the increased risk of adverse events, vaccines containing the Urabe, Hoshino, and Leningrad-Zagreb strains have been withdrawn from use in several countries.

A systematic review in 2003 and two subsequent systematic Cochrane reviews in 2005 and 2012 found that the Urabe mumps strain containing MMR was "likely to be associated with ... aseptic meningitis," whereas the Jeryl Lynn mumps strain containing MMR was "unlikely to be associated with aseptic meningitis" (85; 40; 41). A systematic Cochrane review published in 2021, which included clinical trials and other studies as well as case reports, provides evidence supporting an association between aseptic meningitis and MMR vaccines containing the Urabe and Leningrad-Zagreb mumps strains but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (45). This was an update of an earlier Cochrane review published in 2020 on the same topic, which came to identical conclusions (44).

For economic reasons, countries may continue to use particular vaccines despite recognized adverse outcomes. For example, the Leningrad-Zagreb vaccine strain, which is associated with an increased risk of aseptic meningitis, is widely used in developing countries, costs a fraction of what vaccines cost in the developed world, and is highly effective. Given the relatively benign nature of vaccine-related aseptic meningitis, countries with limited economic means must balance such risks (and whatever adverse effects such outcomes will have on vaccine resistance) against the costs of controlling the target disease (ie, mumps) and the overall benefit provided by their immunization program.

United Kingdom. MMR vaccines containing the Urabe strain of mumps were withdrawn in the United Kingdom in 1992 because the vaccine was associated with an increased risk of aseptic meningitis 15 to 35 days after vaccination.

Cases of aseptic meningitis associated with MMR vaccine were studied in 13 UK health districts following a reported cluster in Nottingham that suggested a risk of 1 in 4000 doses (119). Half of the aseptic meningitis cases identified in children aged 12 to 24 months were vaccine-associated, with onset 15 to 35 days after vaccination. The true risk was substantially higher than the rate suggested by case reports from pediatricians, which was approximately 1 in 11,000 doses. Altogether, 28 vaccine-associated cases were identified, all of which were in recipients of the vaccines containing the Urabe mumps strain (which 86% of the children received); no cases occurred among recipients of the vaccine containing the Jeryl Lynn strain (which about 14% of the children received).

In 1998, a replacement MMR vaccine called Priorix (GlaxoSmithKline, London, UK) was introduced, with a resultant marked reduction in the number of cases of aseptic meningitis. This vaccine uses the RIT 4385 mumps strain, which is derived from the Jeryl Lynn mumps strain. Following the introduction of the replacement MMR vaccine, active surveillance of aseptic meningitis was initiated to assess the risks associated with the new vaccine (118). No laboratory-confirmed cases of mumps meningitis were detected among children aged 12 to 23 months after administration of 1.6 million doses of Priorix in England and Wales (upper 95% confidence limit of risk: 1 per 437,000 doses), a rate significantly lower than with Urabe vaccines (1 per 143,000 doses). Among children aged 12 to 23 months who had received over 99,000 doses of Priorix in a regional database of hospital-admitted cases (upper 95% confidence limit of risk: 1 per 27,000 doses), no cases of aseptic meningitis were detected—a rate significantly lower than with Urabe vaccines (1 per 12,400 doses).

Japan. In Japan, postvaccine aseptic meningitis cases were reported after an MMR vaccine that used the Urabe Am9 mumps strain was added to the routine immunization in April 1989 (176; 129; 141; 148). Among 630,157 recipients of MMR vaccine containing the Urabe Am9 mumps strain, there were at least 311 meningitis cases suspected to be vaccine-related (1 per 2026 doses or 49 per 100,000 doses). In October 1991, three other MMR vaccines became available for the routine immunization program, in addition to the standard vaccine, but postvaccine aseptic meningitis cases continued to be frequently reported. Consequently, the Ministry of Health, Labor and Welfare recommended the suspension of all MMR vaccinations in April 1993, and the mumps vaccine was excluded from the routine immunization program. As a result, the vaccination rate has remained low (around 30%), and mumps continues to be endemic in Japan.

In a prospective cohort study of 21,465 children who received the first of three doses of a Japanese mumps monovalent vaccine during the period 2000 through 2002, there were 10 cases of aseptic meningitis, or 1 per 2147 doses (129). Rates of aseptic meningitis by vaccine strain were 1 per 1570 doses for the Torii strain, 1 per 3379 doses for the Miyahara strain, and 1 per 2282 doses for the Hoshino strain. The cumulative incidence of aseptic meningitis increased significantly with age. In addition, the cumulative incidence of aseptic meningitis in boys was significantly higher than that in girls (1/1302 vs. 1/9746, respectively).

The incidence of post-vaccination aseptic meningitis with the Torii strain monovalent mumps vaccine has declined significantly since 2001 (after changes in the vaccine manufacturing process in 2000), and the incidence has remained stable at fewer than three cases per 100,000 doses since 2010 (138). The incidence of aseptic meningitis (per 100,000 doses) was 7.90 between 1998 and 2000. It declined by half to 3 between 2001 and 2003 and remained stable at 2.78 for the period 2016 to 2018.

From April 2013 to April 2017, 96 cases of postvaccination aseptic meningitis were identified among 4,605,536 doses of monovalent mumps vaccines, giving an incidence of 2.1 cases per 100,000 doses, approximately 1/25 of the prior rates (141). In fiscal years 2010 through 2016 (ie, April 2010 through March 2016), after initiation of a public subsidy program to increase the mumps vaccination rate in Nagoya City, the incidence rate of postvaccination aseptic meningitis was 0.7 cases per 100,000 doses (one patient/140,316 doses).

Although aseptic meningitis is a recognized side effect of the mumps vaccine, the incidence is considerably lower than among those with symptomatic natural infection (130). In a prospective cohort study from 2000 through 2002, the incidence of aseptic meningitis was 13 in 1051 (1 per 81 doses, or 1.24%) in patients with symptomatic natural mumps infection and 10 in 21,465 (1 per 2147 doses, or 0.05%) in vaccine recipients (130).

COVID-19 vaccines. Two cases of drug-induced aseptic meningitis with lymphocytic-predominant CSF pleocytosis following the BNT-162b2 (Pfizer) COVID-19 vaccine have been reported (27). (Another supposed case in a different report did not even meet the case definition for aseptic meningitis.)

Intrathecal drugs and diagnostics

Drug-induced aseptic meningitis is well-documented for multiple medications for this route of administration.

Methotrexate. Drug-induced aseptic meningitis typically becomes evident 2 to 4 hours after intrathecal injection of methotrexate. Meningism is rarely seen after the first injection, but the incidence increases with the number of intrathecal injections and is dose related. Chemical preservatives in the solution may contribute to the meningeal reaction.

Cytarabine. Intrathecal administration of cytarabine for meningeal leukemia is associated with CNS toxicity, including drug-induced aseptic meningitis. This usually occurs in cases where the tumor is resistant to methotrexate. The symptoms and signs are like those of drug-induced aseptic meningitis induced by methotrexate, and because its use follows that of methotrexate, the incidence and predisposing factors are difficult to determine.

Corticosteroids. Intrathecal injections of methylprednisolone acetate have been associated with drug-induced aseptic meningitis (17). Epidural injections of steroids are considered safer, but cases of drug-induced aseptic meningitis have been reported following this procedure as well, perhaps because the subarachnoid space was inadvertently entered.

Baclofen. Drug-induced aseptic meningitis is a rare complication of intrathecal baclofen injections. It is a diagnosis of exclusion, and its pathophysiological mechanism remains unclear (16).

Leflunomide. Leflunomide, a disease-modifying antirheumatic agent, has been reported as a cause of drug-induced aseptic meningitis (109).

Spinal anesthesia. Aseptic meningitis may follow spinal anesthesia due to complications resulting in arachnoiditis: blood in the intrathecal space, introduction of neurotoxic and neuroirritant substances, and surgical interventions on the spine.

Radiologic contrast media. Arachnoiditis was a recognized and fairly common residual effect of the oil-based, iodinated, intrathecal contrast agents in use from the 1920s well into the 1980s. Ethiodized oil (Lipiodol; a combination of iodine and ethyl esters of poppy seed oil) was introduced in 1921 for contrast myelography (which replaced air myelography) by French neurologist and radiologist Jean-Athanase Sicard (1872–1929) and French rheumatologist Jacques Forestier (1890–1978). Subsequently, in 1944, iofendylate (Pantopaque in North America and Myodil elsewhere) was introduced as a contrast medium, and it rapidly became the preferred contrast agent for myelograms when it was found to be less irritating to the meninges than ethiodized oil. However, iofendylate also caused severe arachnoiditis at a disconcerting frequency, and it was ultimately discontinued in 1988 (108) after having been largely superseded by the water-soluble contrast agents that were introduced in the 1970s (eg, metrizamide).

The use of non-ionic water-soluble contrast agents (ie, metrizamide) markedly reduces the incidence of drug-induced aseptic meningitis and arachnoiditis, but such complications have occurred in as many as 5% of cases with metrizamide myelography (96; 185; 13; 64; 23; 39; 46). The introduction of less toxic water-soluble agents further reduced adverse effects, but rare cases of aseptic meningitis were still reported after intrathecal iohexol injection for CT myelography was introduced in the 1980s (31; 158).

Radiolabeled albumin. Drug-induced aseptic meningitis is also described following the use of intrathecal isotopes for diagnostic purposes and as a complication of scinticisternography utilizing 111indium-DTPA and intrathecal injection of radioiodinated serum albumin. Both iodine and albumin could be implicated as causing an "allergic" reaction when injected into the subarachnoid space.

Intraventricular drugs. Drug-induced aseptic meningitis is the most frequent complication of intraventricular chemotherapy for leptomeningeal metastases.

Devices used for the treatment of neurologic disorders

Drug-induced aseptic meningitis has been reported as a complication of hydrogel-coated coils used in the treatment of intracranial aneurysms (83; 93; 48). Reported complications attributed to drug-induced aseptic meningitis in these patients include brain stem and cerebellar infarct (48) as well as delayed hydrocephalus (93).

Differential diagnosis

Confusing conditions

Differential diagnostic considerations for drug-induced aseptic meningitis are shown in Table 2.

Table 2. Differential Diagnosis of Drug-Induced Aseptic Meningitis

Infectious diseases
	• Bacterial meningitis^#
	• Fungal meningitis, eg, Cryptococcus neoformans
	• Parasitic CNS infections, eg, Toxoplasma gondii and cysticercosis
	• Syphilitic meningitis
	• Viral meningitis
		- Arbovirus
		- Enteroviruses, eg, Coxsackie and ECHO viruses
		- Herpes simplex virus 2 (HSV-2)
		- HIV
		- Mumps virus
		- Respiratory viruses, eg, adenovirus, influenza virus, rhinovirus
		- Varicella zoster
		- West Nile virus
Noninfectious diseases
	• Behcet disease
	• Cerebral vasculitis
	• Fabry disease
	• Granulomatosis with polyangiitis (Wegener granulomatosis)
	• Histiocytic necrotizing lymphadenitis (Kikuchi disease) (165)
	• Leptomeningeal malignancy
	• Mollaret meningitis*
	• Rheumatological disorders:
		- Adult-onset Still disease (04)
		- Mixed connective tissue disease
		- Systemic lupus erythematosus
	• Sarcoidosis
	• Skull defects (eg, post-traumatic CSF fistula; iatrogenic)
	• Spontaneous intracranial hypotension (14)
	• Vogt-Koyanagi-Harada syndrome
	^#Partially treated bacterial meningitis should also be considered in the differential diagnosis of aseptic meningitis, especially when the patient has a history of previous oral antimicrobial therapy and when CSF exhibits persistently low glucose or polymorphonuclear pleocytosis.
	* Mollaret meningitis is a form of recurrent aseptic meningitis that is idiopathic, by definition (22; 61). Cases of Mollaret meningitis attributed to HSV-2 would be better called “recurrent lymphocytic meningitis due to HSV-2.”

Drug-induced aseptic meningitis should be considered in the differential diagnosis of acute and recurrent aseptic meningitis. The diagnosis of drug-induced aseptic meningitis is difficult, and in some cases the diagnosis has been confirmed by rechallenging the patient with the suspected agent. Informed written consent is necessary and rechallenge must be medically supervised.

Associated or underlying disorders

The following underlying disorders appear to increase the risk of drug-induced aseptic meningitis but certainly are not required for drug-induced aseptic meningitis to occur:

• Crohn disease
• HIV infection
• Idiopathic thrombocytopenic purpura
• Rheumatoid arthritis
• Sjogren syndrome
• Systemic lupus erythematosus

Diagnostic workup

	• Drug-induced aseptic meningitis cannot be distinguished from infectious meningitis or other causes of noninfectious meningitis strictly based on clinical features or CSF test results.
	• No specific clinical or biological parameters are pathognomonic for drug-induced aseptic meningitis.
	• Drug-induced aseptic meningitis is a diagnosis of exclusion that should only be considered after all infectious causes have been ruled out.
	• The diagnosis of drug-induced aseptic meningitis is made based on close association with a drug and exclusion of other causes of meningitis.
	• If the clinical picture is compatible with bacterial meningitis, antibiotic therapy must be administered until negativity of cultures and other microbiological tests is determined.
	• The diagnosis of drug-induced aseptic meningitis is supported by the following: (1) close association between drug administration and clinical onset of signs and symptoms of meningeal irritation; (2) rapid, spontaneous regression of clinical symptoms after stopping the suspected drug; (3) the presence of comorbid conditions known to be drug-specific risk factors for drug-induced aseptic meningitis (eg, systemic lupus erythematosus with NSAIDs, especially ibuprofen; migraine with IVIG); and (4) recurrence after rechallenge with the suspected drug (although this is NOT generally advised).

In the case definition of aseptic meningitis, criteria 1 to 3 are required, with the level of diagnostic certainty determined by criterion 4 concerning CSF culture results obtained before or after antibiotic therapy is initiated (178).

1. Clinical evidence of acute meningitis, such as fever, headache, vomiting, bulging fontanelle, nuchal rigidity, or other signs of meningeal irritation
2. CSF pleocytosis
	a. > 5 leukocytes/mm3 (µL) if patient is 2 months of age or older
	b. > 15 leukocytes/mm3 (µL) in infants younger than 2 months
3. CSF Gram stain: absence of any microorganism
4. CSF culture results
	a. Level 1 diagnostic certainty: negative routine CSF bacterial culture in the absence of antibiotic treatment before obtaining the first CSF sample
	b. Level 2 diagnostic certainty: no CSF bacterial culture obtained OR negative culture in the presence of antibiotic treatment before obtaining the first CSF sample

Drug-induced aseptic meningitis cannot be distinguished from infectious meningitis or other causes of noninfectious meningitis strictly based on clinical features or CSF test results. The diagnosis is, therefore, based on close association between drug administration and symptoms, signs, and laboratory evidence of meningeal irritation in conjunction with negative microbiology test results (157; 57; 205).

If the clinical picture is compatible with bacterial meningitis, antibiotic therapy must be administered until negativity of cultures and other microbiological tests is determined.

Drug-induced aseptic meningitis is a diagnosis of exclusion that should only be considered after all infectious causes have been ruled out. No specific clinical or biological parameters are pathognomonic for drug-induced aseptic meningitis (205). Although positive drug rechallenge confirms the diagnosis of drug-induced aseptic meningitis by reproducing the symptoms, signs, and CSF indicators of meningeal irritation, it is generally not advised (157; 21). If drug rechallenge is undertaken, informed written consent is necessary and rechallenge must be medically supervised, both to document the response and to provide needed medical care and advice (134).

The diagnosis of drug-induced aseptic meningitis requires that criteria for aseptic meningitis be met (178). The diagnosis is then supported by the following:

	• Close association between drug administration and clinical onset of signs and symptoms of meningeal irritation.
	• Rapid, spontaneous regression of clinical symptoms after stopping the suspected drug.
	• The presence of comorbid conditions known to be drug-specific risk factors for drug-induced aseptic meningitis (eg, systemic lupus erythematosus with NSAID drug-induced aseptic meningitis, especially ibuprofen drug-induced aseptic meningitis; migraine with IVIG drug-induced aseptic meningitis).
	• Recurrence after rechallenge with the suspected drug (this is NOT generally advised).

The peripheral white blood count may be normal or elevated with drug-induced aseptic meningitis.

Lumbar puncture in patients with drug-induced aseptic meningitis usually reveals an elevated opening pressure. CSF examination shows pleocytosis ranging from a hundred to several thousand cells. The predominant cells are usually lymphocytic (205; 05) or polymorphonuclear (155; 125; 21; 92; 99), although uncommon eosinophilic forms of drug-induced aseptic meningitis may occur (155). The variation in CSF cell count distribution may depend on the responsible drug and the pathogenic mechanism involved in that drug-specific hypersensitivity reaction.

CSF proteins are usually elevated. CSF glucose is usually normal but can be low (155). CSF stains and culture results are always negative for microorganisms.

CSF eosinophilia may be (1) reactive (eg, an inflammatory reaction to parasites, medications, or implanted substances); (2) clonal (eg, eosinophilic leukemia); or (3) unexplained (eg, idiopathic hypereosinophilic syndrome). CSF eosinophilia is most frequently associated with a reaction to infectious agents, whereby the occurrence of eosinophilic meningitis is dependent on the localization of parasite structures next to the meninges (70). In the past (1970s and early 1980s), multiple reports described CSF eosinophilia associated with oil-based, iodinated, intrathecal contrast agents (70). Aseptic eosinophilic meningitis has also been associated with IVIG (166; 196). Other, mostly anecdotal, reports of aseptic eosinophilic meningitis in response to medications or materials intentionally placed in the body include the following: ibuprofen, ciprofloxacin, intraventricular gentamicin, intraventricular vancomycin, catheters impregnated with rifampin and minocycline, plastic implants in contact with the meninges, and intraventricular shunts (152; 121; 10; 69; 70).

Human enteroviruses are the most frequent cause of aseptic meningitis. Drug-induced meningitis needs to be differentiated from viral aseptic meningitis, which can be detected by polymerase chain reaction (PCR)-based tests. A real-time reverse transcriptase-quantitative PCR (RT-qPCR) assay is a valuable tool for the diagnosis of enterovirus infection from CSF samples (192).

It is important to differentiate between bacterial meningitis and aseptic meningitis to prevent unnecessary use of antibiotics and hospitalizations. A multicenter, retrospective cohort study has shown that the Bacterial Meningitis Score may be helpful in guiding clinical decision-making for the diagnosis of children presenting to emergency departments with CSF pleocytosis (137). This method classifies patients at very low risk of bacterial meningitis if they lack all the following criteria: positive CSF Gram stain, CSF absolute neutrophil count of at least 1000 cells/microL, CSF protein of at least 80 mg/dL, peripheral blood absolute neutrophil count of at least 10,000 cells/microL, and a history of seizure before or at the time of presentation.

Routine CSF analysis is not a reliable method to differentiate aseptic meningitis from partially treated bacterial meningitis. CSF lactate is a better marker compared to other conventional markers (82), although it has been most often studied in the clinical context of suspected post-neurosurgical bacterial meningitis (113; 105; 204; 206; 107; 100). CSF lactate can differentiate bacterial meningitis (usually > 6 mmol/l) from partially treated meningitis (4 to 6 mmol/l) and aseptic meningitis (usually < 2 mmol/l) (34).

Serum and CSF levels of procalcitonin are elevated in bacterial meningitis, whereas they are normal in viral meningitis (190). They have not been well studied in drug-induced aseptic meningitis.

Table 3. Comparison of CSF Results and Implications for Management and Outcome for the Physiological State, Bacterial Meningitis, Viral Meningitis, and Drug-Induced Aseptic Meningitis

	Physiological state	Bacterial meningitis	Viral meningitis	Drug-induced aseptic meningitis
CSF appearance	Clear
Leukocytes/mm3	< 5	> 1000	usually < 100 (can be up to 1000)	100-2000 (mean approx. 300)
Preponderant leukocyte type	Lymphocytes	Neutrophils	Lymphocytes	Lymphocytes or Neutrophils²
CSF protein	15-45 mg/dL (upper limit may be as high as 60 mg/dl)	Increased (often markedly elevated)	Normal or mildly elevated	Increased
CSF glucose	2/3 of blood level (typically 50 to 80 mg/100 m	Decreased (often marked decrease)	Usually normal¹	Normal (rarely can be low)
CSF Gram stain	Negative	May be positive	Negative	Negative
CSF bacterial culture	Sterile	Positive	Sterile	Sterile
CSF PCR/serology	Negative/Normal	Negative/Normal	May be positive
	Negative/Normal
CSF lactate	< 3.5 mmol/L	≥ 3.5 mmol/L	< 3.5 mmol/L	< 3.5 mmol/L
Management		Antibiotics	Antiviral drugs (possibly)
	Drug discontinuation
Time to resolution of meningeal symptoms and signs		7-21 days	7-15 days	Within 2-3 days
1. Severe hypoglycorrhachia has been reported, especially with lymphocytic choriomeningitis virus (LCMV) or the mumps virus. 2. The predominant cell type varies considerably in different reports and reviews, with some suggesting predominant lymphocytes and others predominant neutrophils. Differences are possibly related to the specific drugs responsible for drug-induced aseptic meningitis and different drug-dependent mechanisms of drug-induced hypersensitivity reactions.

Magnetic resonance imaging. MRI may show periventricular or diffuse supratentorial white matter abnormalities and diffuse meningeal enhancement (after administration of gadolinium) that clear after recovery from drug-induced aseptic meningitis (56; 88; 71).

References

01: Abu Khattab M, Al Soub H, Al Maslamani M, Al Khuwaiter J, El Deeb Y. Herpes simplex virus type 2 (Mollaret's) meningitis: a case report. Int J Infect Dis 2009;13(6):e476-9. PMID 19329344
02: Adair JC, Woodley SL, O'Connell JB, Call GK, Baringer JR. Aseptic meningitis following cardiac transplantation: clinical characteristics and relationship to immunosuppressive regimen. Neurology 1991;41:249-52. PMID 1899475
03: Agabawi S. Trimethoprim-sulfamethoxazole-induced aseptic meningitis: a rare presentation of commonly used antibiotic. Case Rep Infect Dis 2019;2019:4289502. PMID 31885958
04: Akkara Veetil BM, Yee AH, Warrington KJ, Aksamit AJ Jr, Mason TG. Aseptic meningitis in adult onset Still's disease. Rheumatol Int 2012;32(12):4031-4. PMID 20495923
05: Alarcon E, Sansosti A, Navarro B, et al. Amoxicillin-induced aseptic meningitis: 2 case reports and appraisal of the literature. J Investig Allergol Clin Immunol 2019;29(3):248-50.** PMID 31219042
06: Antonen J, Hulkkonen J, Pasternack A, Hurme M. Interleukin 6 may be an important mediator of trimethoprim-induced systemic adverse reaction resembling aseptic meningitis. Arch Intern Med 2000;160(13):2066-7. PMID 10888991
07: Antonen JA, Saha HH, Hurme M, Pasternack AI. IL-6 may be the key mediator in trimethoprim-induced systemic adverse reaction and aseptic meningitis: a reply to Muller et al. Clin Nephrol 2001;55(6):489-90. PMID 11434363
08: Arian M, AkbariRad M, Moghaddam AB, Firoozi A, Jami M. Allopurinol and loss of consciousness in a 78-old year man suffering from gout. Infect Disord Drug Targets 2020;20(2):253-6. PMID 30686265
09: Ashwath ML, Katner HP. Recurrent aseptic meningitis due to different non-steroidal anti-inflammatory drugs including rofecoxib. Postgrad Med J 2003;79(931):295-6. PMID 12782779
10: Asperilla MO, Smego RA Jr. Eosinophilic meningitis associated with ciprofloxacin. Am J Med 1989;87(5):589-90. PMID 2816976
11: Audemard A, Le Bellec ML, Carluer L, et al. Fumagillin-induced aseptic meningoencephalitis in a kidney transplant recipient with microsporidiosis. Transpl Infect Dis 2012;14(6):E147-9. PMID 23025483
12: Bachmeyer C, de la Blanchardière A, Lepercq J, et al. Recurring episodes of meningitis (Mollaret's meningitis) with one showing an association with herpes simplex virus type 2. J Infect 1996;32(3):247-8. PMID 8793718
13: Baker FJ, Gossen G, Bertoni JM. Aseptic meningitis complicating metrizamide myelography. AJNR Am J Neuroradiol 1982;3(6):662-3. PMID 6816043
14: Balkan II, Albayram S, Ozaras R, et al. Spontaneous intracranial hypotension syndrome may mimic aseptic meningitis. Scand J Infect Dis 2012;44(7):481-8. PMID 22404365
15: Barrett PV, Thier SO. Meningitis and pancreatitis associated with sulfamethizole. N Engl J Med 1963;268:36-7. PMID 13969534
16: Bensmail D, Peskine A, Denys P, Bernard L, Bussel B. Aseptic meningitis after intrathecal baclofen injection. Spinal Cord 2006;44(5):330-3. PMID 16172626
17: Bernat JL, Sadowsky CH, Vincent FM, Nordgren RE, Margolis G. Sclerosing spinal pachymeningitis. A complication of intrathecal administration of Depo-Medrol for multiple sclerosis. J Neurol Neurosurg Psychiatry 1976;39(11):1124-8. PMID 1037000
18: Bharath V, Eckert K, Kang M, Chin-Yee IH, Hsia CC. Incidence and natural history of intravenous immunoglobulin-induced aseptic meningitis: a retrospective review at a single tertiary care center. Transfusion 2015;55(11):2597-605. PMID 26095012
19: Bihan K, Weiss N, Théophile H, Funck-Brentano C, Lebrun-Vignes B. Drug-induced aseptic meningitis: 329 cases from the French pharmacovigilance database analysis. Br J Clin Pharmacol 2019;85(11):2540-6.** PMID 31318079
20: Bonnet MC, Dutta A, Weinberger C, Plotkin SA. Mumps vaccine virus strains and aseptic meningitis. Vaccine 2006;24(49-50):7037-45. PMID 16884835
21: Bruner KE, Coop CA, White KM. Trimethoprim-sulfamethoxazole-induced aseptic meningitis-not just another sulfa allergy. Ann Allergy Asthma Immunol 2014;113(5):520-6.** PMID 25240332
22: Bruyn G, Straathof LJ, Raymakers G. Mollaret’s meningitis: differential diagnosis and diagnostic pitfalls. Neurology 1962;12:745-53. PMID 14016408
23: Budny JL, Hopkins LN. Ventriculitis after metrizamide lumbar myelography. Neurosurgery 1985;17(3):467-8. PMID 4047357
24: Capone PM, Cohen ME. Seizures and cerebritis associated with administration of OKT3. Pediatr Neurol 1991;7(4):299-301. PMID 1930424
25: Chalimou I, Krilis A, Anastopoulou GG, et al. Acute aseptic meningitis during isotretinoin treatment for nodular acne solely presenting with headache: case report and brief review of the literature. Int J Neurosci 2019;129(2):204-6. PMID 30160569
26: Chamberlain MC, Kormanik PA, Barba D. Complications associated with intraventricular chemotherapy in patients with leptomeningeal metastases. J Neurosurg 1997;87(5):694-9. PMID 9347977
27: Chan AC, Tan BY, Goh Y, Tan SS, Tambyah PA. Aseptic meningitis after BNT-162b2 COVID-19 vaccination. Brain Behav Immun Health 2022;19:100406. PMID 34927105
28: Chand S, Thapa S, Gautam K, Twayana AR, Laguio-Vila MR, Elsourbagy T. Benign recurrent aseptic meningitis (Mollaret's meningitis) in an elderly male: a case report. JNMA J Nepal Med Assoc 2021;59(241):916-8. PMID 35199717
29: Chandler RE. Increased risk for aseptic meningitis after amoxicillin or amoxicillin-clavulanic acid in males: a signal revealed by subset disproportionality analysis within a global database of suspected adverse drug reactions. Pharmacoepidemiol Drug Saf 2019;28(3):389-95. PMID 30556617
30: Chez M, Sila CA, Ransohoff RM, Longworth DL, Weida C. Ibuprofen-induced meningitis: detection of intrathecal IgG synthesis and immune complexes. Neurology 1989;39(12):1578-80. PMID 2586773
31: Cissoko H, Lemesle F, Jonville-Bera AP, Autret-Leca E. Aseptic meningitis after iohexol myelography. Ann Pharmacother 2000;34(6):812-3. PMID 10860145
32: Colamarino R, Soubrier M, Zenut-Léaud M, Prudat M, Tournilhac M, Bussiere JL. [Aseptic meningitis caused by ibuprofen (Nurofen) in connective tissue diseases]. Therapie 1993;48(5):516-8. PMID 8146853
33: Creel GB, Hurtt M. Cephalosporin-induced recurrent aseptic meningitis. Ann Neurol 1995;37(6):815-7. PMID 7778857
34: Cunha BA. Distinguishing bacterial from viral meningitis: the critical importance of the CSF lactic acid levels. Intensive Care Med 2006;32(8):1272-3; Intensive Care Med 2006;32(8):1272-3. PMID 16770614
35: Cushing H, Bailey P. Tumors arising from the blood-vessels of the brain: angiomatous malformations and hemangioblastomas. Springfield, Ill: Charles C Thomas, 1928.
36: da Silveira CM, Kmetzsch CI, Mohrdieck R, Sperb AF, Prevots DR. The risk of aseptic meningitis associated with the Leningrad-Zagreb mumps vaccine strain following mass vaccination with measles-mumps-rubella vaccine, Rio Grande do Sul, Brazil, 1997. Int J Epidemiol 2002;31(5):978-82. PMID 12435771
37: Damsgaard J, Hjerrild S, Andersen H, Leutscher PD. Long-term neuropsychiatric consequences of aseptic meningitis in adult patients. Infect Dis (Lond) 2015;47(6):357-63. PMID 25738613
38: Dang CT, Riley DK. Aseptic meningitis secondary to carbamazepine therapy. Clin Infect Dis 1996;22(4):729-30. PMID 8729227
39: de Weerdt CJ, van de Poll MA. [Aseptic meningitis after use of Amipaque]. Ned Tijdschr Geneeskd 1980;124(42):1783-4. PMID 7432567
40: Demicheli V, Jefferson T, Rivetti A, Price D. Vaccines for measles, mumps and rubella in children. Cochrane Database Syst Rev 2005;(4):CD004407. PMID 16235361
41: Demicheli V, Rivetti A, Debalini MG, Di Pietrantonj C. Vaccines for measles, mumps and rubella in children. Cochrane Database Syst Rev 2012;2012(2):CD004407. PMID 22336803
42: Desgranges F, Tebib N, Lamy O, Kritikos A. Meningitis due to non-steroidal anti-inflammatory drugs: an often-overlooked complication of a widely used medication. BMJ Case Rep 2019;12(11):e231619. PMID 31704799
43: DeVault GA Jr, Kohan DE, Nelson EW, Holman Jr JM. The effects of oral pentoxifylline on the cytokine release syndrome during inductive OKT3. Transplantation 1994;57(4):532-40. PMID 8116037
44: Di Pietrantonj C, Rivetti A, Marchione P, Debalini MG, Demicheli V. Vaccines for measles, mumps, rubella, and varicella in children. Cochrane Database Syst Rev 2020;4(4):CD004407. PMID 32309885
45: Di Pietrantonj C, Rivetti A, Marchione P, Debalini MG, Demicheli V. Vaccines for measles, mumps, rubella, and varicella in children. Cochrane Database Syst Rev 2021;11(11):CD004407.** PMID 34806766
46: DiMario Jr FJ. Aseptic meningitis secondary to metrizamide lumbar myelography in a 4 1/2-month-old infant. Pediatrics 1985;76(2):259-62. PMID 4022701
47: Doghmi N, Meskine A, Benakroute A, Bensghir M, Baite A, Haimeur C. Aseptic meningitis following a bupivacaine spinal anesthesia. Pan Afr Med J 2017;27:192. PMID 28904717
48: Donmez H, Mavili E, Ikizceli T, Durak AC, Kurtsoy A. Stroke secondary to aseptic meningitis after endovascular treatment of a giant aneurysm with parent artery occlusion. Cardiovasc Intervent Radiol 2009;32(4):801-3. PMID 19194746
49: Dourado I, Cunha S, Teixeira MG, et al. Outbreak of aseptic meningitis associated with mass vaccination with a urabe-containing measles-mumps-rubella vaccine: implications for immunization programs. Am J Epidemiol 2000;151(5):524-30. PMID 10707922
50: Duchene DA, Smith CP, Goldfarb RA. Allopurinol induced meningitis. J Urol 2000;164(6):2028. PMID 11061913
51: Durback MA, Freeman J, Schumacher VR Jr. Recurrent ibuprofen-induced aseptic meningitis: third episode after only 200 mg of generic ibuprofen. Arthritis Rheum 1988;31(6):813-5. PMID 3382456
52: Dylewski JS, Bekhor S. Mollaret's meningitis caused by herpes simplex virus type 2: case report and literature review. Eur J Clin Microbiol Infect Dis 2004;23(7):560-2. PMID 15221615
53: Elmedani S, Albayati A, Udongwo N, Odak M, Khawaja S. Trimethoprim-sulfamethoxazole-induced aseptic meningitis: a new approach. Cureus 2021;13(6):e15869. PMID 34327094
54: Emani MK, Zaiden RA Jr. Aseptic meningitis: a rare side effect of cetuximab therapy. J Oncol Pharm Pract 2013;19(2):178-80. PMID 22623275
55: Escalante A, Stimmler MM. Trimethoprim-sulfamethoxasole induced meningitis in systemic lupus erythematosus. J Rheumatol 1992;19(5):800-2. PMID 1613713
56: Eustace S, Buff B. Magnetic resonance imaging in drug-induced meningitis. Can Assoc Radiol J 1994;45(6):463-5. PMID 7982109
57: Farr KP, Mogensen CB. Drug-induced aseptic meningitis. [Article in Danish] Ugeskr Laeger 2010;172(4):298-9. PMID 20105400
58: Faurie P, Pérard L, Hot A, et al. Recurrent aseptic meningitis secondary to nonsteroidal anti-inflammatory drugs in a patient with lupus. [Article in French] Rev Med Interne 2010;31(10):e1-3. PMID 20541295
59: Fisher JH, Sydney MB. Encephalomyelitis following administration of sulfanilamide. Lancet 1939;1:301-5.
60: Foley RW, Tagg NT, Schindler MK, et al. Recurrent natalizumab-related aseptic meningitis in a patient with multiple sclerosis. Mult Scler 2017;23(10):1424-7. PMID 28639536
61: Frederiks JA, Bruyn GW. Mollaret's meningitis. In: McKendall RR, editor. Handbook of clinical neurology. Vol 12. Viral disease. Amsterdam: Elsevier Science Publishers, 1989:627-35.
62: Freyer CW, Yaghmour G, Jennings K, Dhanapal V. Drug-induced aseptic meningitis associated with intrathecal trastuzumab. J Pharm Technol 2014;30(2):43-7. PMID 34860873
63: Galdi AP. Benign recurrent aseptic meningitis (Mollaret's meningitis): case report and clinical review. Arch Neurol 1979;36(10):657-8. PMID 485900
64: Gelmers HJ. Exacerbation of systemic lupus erythematosus, aseptic meningitis and acute mental symptoms, following metrizamide lumbar myelography. Neuroradiology 1984;26(1):65-6. PMID 6738846
65: Gilbert GJ, Eichenbaum HW. Ibuprofen-induced meningitis in an elderly patient with systemic lupus erythematosus. South Med J 1989;82(4):514-5. PMID 2705078
66: Gluck L, Robbins M, Galen B. Mollaret cells in recurrent benign lymphocytic meningitis. Neurohospitalist 2019;9(1):49-50. PMID 30671166
67: Goldfield M, Weinstein L. Meningismus in pneumonia. BMQ 1952;3(3):70-4. PMID 12987378
68: Goyal T, Ali I. Recurrent herpes simplex virus 2 lymphocytic meningitis in patient with IgG subclass 2 deficiency. Emerg Infect Dis 2020;26(4):748-50. PMID 32186491
69: Grabb PA, Albright AL. Intraventricular vancomycin-induced cerebrospinal fluid eosinophilia: report of two patients. Neurosurgery 1992;30(4):630-4. PMID 1584367
70: Graeff-Teixeira C, da Silva ACA, Yoshimura K. Update on eosinophilic meningoencephalitis and its clinical relevance. Clin Microbiol Rev 2009;22(2):322-48. PMID 19366917
71: Green MA, Abraham MN, Horn AJ, Yates TE, Egbert M, Sharma A. Lamotrigine-induced aseptic meningitis: a case report. Int Clin Psychopharmacol 2009;24(3):159-61. PMID 19357526
72: Greenberg LE, Nguyen T, Miller SM. Suspected allopurinol-induced aseptic meningitis. Pharmacotherapy 2001;21(8):1007-9. PMID 11718488
73: Griffith BP, Kormos RL, Armitage JM, Dummer JS, Hardesty RL. Comparative trial of immunoprophylaxis with RATG versus OKT3. J Heart Transplant 1990;9(3 Pt 2):301-5. PMID 2113093
74: Hanson L. Ibuprofen-induced aseptic meningitis. J Tenn Med Assoc 1994;87(2):58. PMID 8176914
75: Helbok R, Broessner G, Pfausler B, Schmutzhard E. Chronic meningitis. J Neurol 2009;256(2):168-75. PMID 19224317
76: Hemet C, Chassagne P, Levade MH, et al. Aseptic meningitis secondary to carbamazepine treatment of manic-depressive illness. Am J Psychiatry 1994;151(9):1393. PMID 8067500
77: Hidalgo Natera A, Cárdenas Contreras R, Najem Risk N, Canto Díez G. Ibuprofen, aseptic meningitis, systemic lupus erythematosus. Med Clin (Barc) 2004;122(17):678-9. PMID 15153354
78: Hilton E, Stroh EM. Aseptic meningitis associated with administration of carbamazepine. J Infect Dis 1989;159(2):363-4. PMID 2915162
79: Hoffman M, Gray RG. Ibuprofen-induced meningitis in mixed connective tissue disease. Clin Rheumatol 1982;1(2):128-30. PMID 6985377
80: Holle D, Obermann M. Headache in drug-induced aseptic meningitis. Curr Pain Headache Rep 2015;19(7):29. PMID 26049774
81: Horn AC, Jarrett SW. Ibuprofen-induced aseptic meningitis in rheumatoid arthritis. Ann Pharmacother 1997;31(9):1009-11. PMID 9296242
82: Huy NT, Thao NTH, Diep DT, Kikuchi M, Zamora J, Hirayama K. Cerebrospinal fluid lactate concentration to distinguish bacterial from aseptic meningitis: a systemic review and meta-analysis. Crit Care 2010;14(6):R240. PMID 21194480
83: Im SH, Han MH, Kwon BJ, Jung C, Kim JE, Han DH. Aseptic meningitis after embolization of cerebral aneurysms using hydrogel-coated coils: report of three cases. AJNR Am J Neuroradiol 2007;28(3):511-2. PMID 17353325
84: Jazeron A, Lallier JC, Rihn B, Thiercelin MC. Aseptic meningitis possibly induced by adalimumab. Joint Bone Spine 2010;77(6):618-9. PMID 20656540
85: Jefferson T, Price D, Demicheli V, et al. Unintended events following immunization with MMR: a systematic review. Vaccine 2003;21(25-26):3954-60. PMID 12922131
86: Jensen S, Glud TK, Bacher T, Ersgaard H. Ibuprofen-induced meningitis in a male with systemic lupus erythematosus. Acta Med Scand 1987;221(5):509-11. PMID 3604762
87: Jha P, Stromich J, Cohen M, Wainaina JN. A rare complication of trimethoprim-sulfamethoxazole: drug induced aseptic meningitis. Case Rep Infect Dis 2016;2016:3879406. PMID 27579194
88: Jolles S, Sewell WA, Leighton C. Drug-induced aseptic meningitis: diagnosis and management. Drug Saf 2000;22(3):215-26. PMID 10738845
89: Jonville-Bera AP, Autret E, Galy-Eyraud C, Hessel L. Aseptic meningitis following mumps vaccine. A retrospective survey by the French Regional Pharmacovigilance centres and by Pasteur-Mérieux Sérums & Vaccins. Pharmacoepidemiol Drug Saf 1996;5(1):33-7. PMID 15088275
90: Junga Z, Theeler B, Singla M. Infliximab-induced aseptic meningitis in a patient with Crohn's disease. ACG Case Rep J 2018;5:e48. PMID 29951563
91: Kageyama T, Isohisa A, Mori N, Suenaga T. Contrast-enhanced magnetic resonance imaging in carbamazepine-induced aseptic meningitis. Cephalalgia 2015;35(14):1333. PMID 25767088
92: Kalmi G, Javeri F, Vanjak A, et al. Drug-induced meningitis: a review of the literature and comparison with an historical cohort of viral meningitis cases. Therapie 2020;75(6):605-15.** PMID 33187718
93: Kang HS, Han MH, Lee TH, et al. Embolization of intracranial aneurysms with hydrogel-coated coils: result of a Korean multicenter trial. Neurosurgery 2007;61(1):51-8. PMID 17621018
94: Karmacharya P, Mainali NR, Aryal MR, Lloyd B. Recurrent case of ibuprofen-induced aseptic meningitis in mixed connective tissue disease. BMJ Case Rep 2013;2013:bcr2013009571. PMID 23632618
95: Kawabori M, Kurisu K, Niiya Y, Ohta Y, Mabuchi S, Houkin K. Mollaret meningitis with a high level of cytokines in the cerebrospinal fluid successfully treated by indomethacin. Intern Med 2019;58(8):1163-6. PMID 30568139
96: Kelley RE, Daroff RB, Sheremata WA, McCormick JR. Unusual effects of metrizamide lumbar myelography. Constellation of aseptic meningitis, arachnoiditis, communicating hydrocephalus, and Guillaine-Barré syndrome. Arch Neurol 1980;37(9):588-9. PMID 7417062
97: Khawcharoenporn T, Apisarnthanarak A, Mundy LM. Intrathecal colistin for drug-resistant Acinetobacter baumannii central nervous system infection: a case series and systematic review. Clin Microbiol Infect 2010;16(7):888-94. PMID 19686281
98: Ki M, Park T, Yi SG, Oh JK, Choi B. Risk analysis of aseptic meningitis after measles-mumps-rubella vaccination in Korean children by using a case-crossover design. Am J Epidemiol 2003;157(2):158-65. PMID 12522023
99: Kretowska-Grunwald A, Krawczuk-Rybak M, Sawicka-Zukowska M. Intravenous immunoglobulin-induced aseptic meningitis-a narrative review of the diagnostic process, pathogenesis, preventative measures and treatment. J Clin Med 2022;11(13):3571. PMID 35806861
100: Kul G, Sencan I, Kul H, Korkmaz N, Altunay E. The role of cerebrospinal fluid biomarkers in the diagnosis of post-neurosurgical meningitis. Turk Neurosurg 2020;30(4):513-9. PMID 31099887
101: Kupila L, Vainionpää R, Vuorinen T, Marttila RJ, Kotilainen P. Recurrent lymphocytic meningitis: the role of herpesviruses. Arch Neurol 2004;61(10):1553-7. PMID 15477509
102: Lawson JM, Grady MJ. Ibuprofen-induced aseptic meningitis in a previously healthy patient. West J Med 1985;143(3):386-7. PMID 4049858
103: Lee RZ, Hardiman O, O'Connell PG. Ibuprofen-induced aseptic meningoencephalitis. Rheumatology (Oxford) 2002;41(3):353-5. PMID 11934981
104: Lenfant C, Greiner N, Duprez T. Cytarabine-induced encephalitis. J Belg Soc Radiol 2021;105(1):46. PMID 34611580
105: Li Y, Zhang G, Ma R, et al. The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of post-neurosurgical bacterial meningitis and aseptic meningitis. Clin Biochem 2015;48(1-2):50-4. PMID 25445228
106: Longcope WT. Serum sickness and analogous reactions from certain drugs particularly the sulfonamides. Medicine 1943;22:251-86.
107: Lotfi R, Ines B, Aziz DM, Mohamed B. Cerebrospinal fluid lactate as an indicator for post-neurosurgical bacterial meningitis. Indian J Crit Care Med 2019;23(3):127-30. PMID 31097888
108: Lutters B, Groen RJM, Koehler PJ. Myelography and the 20th century localization of spinal cord lesions. Eur Neurol 2020;83(4):447-52.** PMID 32871581
109: Mader L, Kollmar R, Lorenz HM. Leflunomide as cause of aseptic meningitis. J Clin Rheumatol 2021;27(8S)S721-2. PMID 32976202
110: Mandell BF, Raps EC. Severe systemic hypersensitivity reaction to ibuprofen occurring after prolonged therapy. Am J Med 1987;82(4):817-20. PMID 3565435
111: Marinac JS. Drug- and chemical-induced aseptic meningitis: a review of the literature. Ann Pharmacother 1992;26(6):813-22. PMID 1611165
112: Martin MA, Massanari RM, Nghiem DD, Smith JL, Corry RJ. Nosocomial aseptic meningitis associated with administration of OKT3. JAMA 1988;259(13):2002-5. PMID 3126308
113: Maskin LP, Capparelli F, Mora A, et al. Cerebrospinal fluid lactate in post-neurosurgical bacterial meningitis diagnosis. Clin Neurol Neurosurg 2013;115(9):1820-5. PMID 23810183
114: Matsui T, Nakagawa K, Yamazaki K, Wada T, Kadoya M, Kaida K. An anti-RNP antibody-positive case of aseptic meningitis induced by non-steroidal anti-inflammatory drugs in a young woman. [Article in Japanese] Rinsho Shinkeigaku 2018;58(1):25-9. PMID 29269694
115: McDaniel EL, Ferguson TM, Kwon HP, Thompson JC. Benign recurrent lymphocytic meningitis from herpes simplex virus type 2 during a summer outbreak of aseptic meningitis. Mil Med 2004;169(6):448-50. PMID 15281674
116: Mifsud AJ. Drug-related recurrent meningitis. J Infect 1988;17(2):151-3. PMID 3183406
117: Mikdashi J, Kennedy S, Krumholz A. Recurrent benign lymphocytic (mollaret) meningitis in systemic lupus erythematosus. Neurologist 2008;14(1):43-5. PMID 18195657
118: Miller E, Andrews N, Stowe J, Grant A, Waight P, Taylor B. Risks of convulsion and aseptic meningitis following measles-mumps-rubella vaccination in the United Kingdom. Am J Epidemiol 2007;165(6):704-9. PMID 17204517
119: Miller E, Goldacre M, Pugh S, et al. Risk of aseptic meningitis after measles, mumps, and rubella vaccine in UK children. Lancet 1993;341(8851):979-82. PMID 8096942
120: Min DI, Monaco AP. Complications associated with immunosuppressive therapy and their management. Pharmacotherapy 1991;11(5):119S-25S. PMID 1745617
121: Mine S, Sato A, Yamaura A, Tamachi S, Makino H, Tomioka H. Eosinophilia of the cerebrospinal fluid in a case of shunt infection: case report. Neurosurgery 1986;19(5):835-6. PMID 3785637
122: Mollaret MP. La meningite endothelio-leucocytaire multirecurrente benigne syndrome nouveau ou maladie nouvelle. Rev Neurol 1944;76:57-76.
123: Moreno-Ancillo A, Gil-Adrados AC, Jurado-Palomo J. Ibuprofen-induced aseptic meningoencephalitis confirmed by drug challenge. J Investig Allergol Clin Immunol 2011;21(6):484-7. PMID 21995183
124: Morgan A, Clark D. CNS adverse effects of nonsteroidal anti-inflammatory drugs: therapeutic implications. CNS Drugs 1998;9(4):281-90. PMID 27521013
125: Moris G, Garcia-Monco JC. The challenge of drug-induced aseptic meningitis. Arch Intern Med 1999;159(11):1185-94.** PMID 10371226
126: Mou SS, Punaro L, Antón J, Luckett PM. Severe systemic hypersensitivity reaction to ibuprofen: a presentation of systemic lupus erythematosus. J Rheumatol 2006;33(1):171-2. PMID 16292790
127: Mousavi Mirzaei S, Ahmadi Z. Ibuprofen-induced aseptic meningitis in a male adolescent with intracranial hypertension and visual impairment: a case report. Case Rep Neurol 2021;13(1):233-8. PMID 33976661
128: Mullane D, Williams L, Merwick A, Tobin WO, McGuigan C. Drug induced aseptic meningitis caused by intravenous immunoglobulin therapy. Ir Med J 2012;105(6):182-3. PMID 22973657
129: Muta H, Nagai T, Ito Y, Ihara T, Nakayama T. Effect of age on the incidence of aseptic meningitis following immunization with monovalent mumps vaccine. Vaccine 2015;33(45):6049-53. PMID 26431987
130: Nagai T, Okafuji T, Miyazaki C, et al. A comparative study of the incidence of aseptic meningitis in symptomatic natural mumps patients and monovalent mumps vaccine recipients in Japan. Vaccine 2007;25(14):2742-7. PMID 16530894
131: Nagovskiy N, Agarwal M, Allerton J. Cetuximab-induced aseptic meningitis. J Thorac Oncol 2010;5(5):751. PMID 20421770
132: Nakajima W, Ishida A, Takahashi M, Sato Y, Ito T, Takada G. Aseptic meningitis associated with cephalosporins in an infant with trisomy 21. J Child Neurol 2007;22(6):780-2. PMID 17641271
133: Nayudu SK, Kavuturu S, Niazi M, Daniel M, Dev A, Kumbum K. A rare coexistence: drug induced hepatitis and meningitis in association with Ibuprofen. J Clin Med Res 2013;5(3):243-6. PMID 23671551
134: Nettis E, Calogiuri G, Colanardi MC, Ferrannini A, Tursi A. Drug-induced aseptic meningitis. Curr Drug Targets Immune Endocr Metabol Disord 2003;3(2):143-9.** PMID 12769786
135: Nguyen HT, Juurlink DN. Recurrent ibuprofen-induced aseptic meningitis. Ann Pharmacother 2004;38(3):408-10. PMID 14742833
136: Nicolosi A, Hauser WA, Beghi E, Kurland LT. Epidemiology of central nervous system infections in Olmsted County, Minnesota, 1950-1981. J Infect Dis 1986;154(3):399-408. PMID 3734490
137: Nigrovic LE, Kuppermann N, Macias CG, et al. Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis. JAMA 2007;297(1):52-60. PMID 17200475
138: Ohfuji S, Tanaka T, Nakano T, et al. Annual trends in adverse events following mumps vaccination in Japan: a retrospective study. Vaccine 2022;40(7):988-93. PMID 35058077
139: Oostenbrink R, Moons KG, Donders AR, Grobbee DE, Moll HA. Prediction of bacterial meningitis in children with meningeal signs: reduction of lumbar punctures. Acta Paediatr 2001b;90(6):611-7.** PMID 11440091
140: Oostenbrink R, Moons KG, Theunissen CC, Derksen-Lubsen G, Grobbee DE, Moll HA. Signs of meningeal irritation at the emergency department: how often bacterial meningitis? Pediatr Emerg Care 2001a;17(3):161-4.** PMID 11437138
141: Ozaki T, Goto Y, Nishimura N, et al. Effects of a public subsidy program for mumps vaccine on reducing the disease burden in Nagoya City, Japan. Jpn J Infect Dis 2019;72(2):106-11. PMID 30381683
142: Pearce JMS. Mollaret's meningitis. Eur Neurol 2008;60(6):316-7. PMID 18832846
143: Pease CL, Horton TM, McClain KL, Kaplan SL. Aseptic meningitis in a child after systemic treatment with high dose cytarabine. Pediatr Infect Dis J 2001;20(1):87-9. PMID 11176579
144: Peltola H, Kulkarni PS, Kapre SV, Paunio M, Jadhav SS, Dhere RM. Mumps outbreaks in Canada and the United States: time for new thinking on mumps vaccines. Clin Infect Dis 2007;45(4):459-66. PMID 17638194
145: Perez-Vilar S, Weibel D, Sturkenboom M, et al. Enhancing global vaccine pharmacovigilance: proof-of-concept study on aseptic meningitis and immune thrombocytopenic purpura following measles-mumps containing vaccination. Vaccine 2018;36(3):347-54. PMID 28558983
146: Periard D, Mayor C, Aubert V, Spertini F. Recurrent ibuprofen-induced aseptic meningitis: evidence against an antigen-specific immune response. Neurology 2006;67(3):539-40. PMID 16894131
147: Pires SAP, Lemos AP, Pereira EPMN, Maia PADSV, Agro JPSEABD. Ibuprofen-induced aseptic meningitis: a case report. Rev Paul Pediatr 2019;37(3):382-5. PMID 31166468
148: Platt H, Tochihara S, Oda Y, Ueda K. The immunogenicity and safety profile for KM-248, a combined measles, mumps, and rubella vaccine, and its noninferiority to the measles vaccine in healthy Japanese children: a phase 3 randomized multicenter single-blind clinical trial. Jpn J Infect Dis 2021;74(5):429-36. PMID 33518626
149: Ploegstra WM, Onnes B, de Vries NKS, Kamps AWA. Occult pneumonia in a child. BMJ Case Rep 2012;2012:bcr0120125521. PMID 22684827
150: Poulikakos PJ, Sergi EE, Margaritis AS, et al. A case of recurrent benign lymphocytic (Mollaret's) meningitis and review of the literature. J Infect Public Health 2010;3(4):192-5. PMID 21126724
151: Prieto-Gonzalez S, Escoda R, Coloma E, Grau JM. Amoxicillin-induced acute aseptic meningitis. J Clin Neurosci 2011;18(3):443-4. PMID 21239175
152: Quinn JP, Weinstein RA, Caplan LR. Eosinophilic meningitis and ibuprofen therapy. Neurology 1984;34(1):108-9. PMID 6537831
153: Rebiere I, Galy-Eyraud C. Estimation of the risk of aseptic meningitis associated with mumps vaccination, France, 1991-1993. Int J Epidemiol 1995;24(6):1223-7. PMID 8824866
154: Rello J, Vallverdú I, Coll P, Gurguí M, Net A. Aseptic meningitis associated with muromonab-CD3. DICP 1990;24(12):1233. PMID 2151004
155: River Y, Averbuch-Heller L, Weinberger M, et al. Antibiotic induced meningitis. J Neurol Neurosurg Psychiatry 1994;57(6):705-8. PMID 8006651
156: Rizzo JD, Rowe SA. Meningism in a ten-month-old infant during OKT3 therapy. J Heart Transplant 1990;9(6):727-8. PMID 2126036
157: Rodriguez SC, Olguín AM, Miralles CP, Viladrich PF. Characteristics of meningitis caused by ibuprofen: report of 2 cases with recurrent episodes and review of the literature. Medicine (Baltimore) 2006;85(4):214-20.** PMID 16862046
158: Romesburg J, Ragozzino M. Aseptic meningoencephalitis after iohexol CT myelography. AJNR Am J Neuroradiol 2009;30(5):1074-5. PMID 19039046
159: Rowley D, Houlihan L, McFaul K, Clarke S, Lyons F. A diagnostic dilemma: drug-induced aseptic meningitis in a 45-year-old HIV-positive man. Int J STD AIDS 2014;25(4):309-11. PMID 23999938
160: Ruppert GB, Barth WF. Ibuprofen hypersensitivity in systemic lupus erythematosus. South Med J 1981a;74(2):241-3. PMID 7466447
161: Ruppert GB, Barth WF. Tolmetin-induced aseptic meningitis. JAMA 1981b;245(1):67-8. PMID 7431632
162: Samuelson CO Jr, Williams HJ. Ibuprofen-associated aseptic meningitis in systemic lupus erythematosus. West J Med 1979;131(1):57-9. PMID 483800
163: Schlipkoter U, Mühlberger N, von Kries R, Weil J. Surveillance of measles-mumps-rubella vaccine-associated aseptic meningitis in Germany. Infection 2002;30(6):351-5. PMID 12478324
164: Sehgal A, Pokhrel E, Castro WR, Haas CJ. Mollaret's meningitis: a rare entity. Cureus 2021;13(5):e15264. PMID 34189002
165: Sekiguchi S, Yamamoto Y, Hatakeyama S, Matsumura M. Recurrent aseptic meningitis associated with Kikuchi's disease (histiocytic necrotizing lymphadenitis): a case report and literature review. Intern Med 2021;60(11):1779-84. PMID 33431735
166: Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994;121(4):259-62. PMID 8037406
167: Shahien R, Vieksler V, Bowirrat A. Amoxicillin-induced aseptic meningoencephalitis. Int J Gen Med 2010;3:157-62. PMID 20689687
168: Shalabi M, Whitley RJ. Recurrent benign lymphocytic meningitis. Clin Infect Dis 2006;43(9):1194-7. PMID 17029141
169: Shapiro WR, Young DF. Neurological complications of antineoplastic therapy. Acta Neurol Scand Suppl 1984;100:125-32. PMID 6385604
170: Shoenfeld Y, Livni E, Shaklai M, Pinkhas J. Sensitization to ibuprofen in systemic lupus erythematosus. JAMA 1980;244(6):547-8. PMID 7392147
171: Simms KM, Kortepeter C, Avigan M. Lamotrigine and aseptic meningitis. Neurology 2012;78(12):921-7. PMID 22357718
172: Simon LT, Hsu B, Adornato BT. Carbamazepine-induced aseptic meningitis. Ann Intern Med 1990;112(8):627-8. PMID 2327680
173: Sonnenblick M, Abraham AS. Ibuprofen hypersensitivity in systemic lupus erythematosus. Br Med J 1978;1(6113):619-20. PMID 630258
174: Sousa D, Raimundo P. Amoxicillin-induced aseptic meningitis. Eur J Case Rep Intern Med 2020;7(6):001543. PMID 32523916
175: Strominger MB, Liu GT, Schatz NJ. Optic disk swelling and abducens palsies associated with OKT3. Am J Ophthalmol 1995;119(5):664-5. PMID 7733200
176: Sugiura A, Yamada A. Aseptic meningitis as a complication of mumps vaccination. Pediatr Infect Dis J 1991;10(3):209-13. PMID 2041668
177: Sutton JD, Prioleau MH, Wordell CJ, Francos GC. Aseptic meningitis associated with muromonab CD3 administration. DICP 1989;23(3):257-8. PMID 2497597
178: Tapiainen T, Prevots R, Izurieta HS, et al. Aseptic meningitis: case definition and guidelines for collection, analysis and presentation of immunization safety data. Vaccine 2007;25(31):5793-802. PMID 17574313
179: Thilmann AF, Mobius E, Thilmann RR, Topper R. Recurrent aseptic meningitis (Mollaret meningitis)—spontaneous and drug-induced origin. Fortschr Neurol Psychiat 1991;59(12):493-7. PMID 1774010
180: Thordarson H, Talstad I. Acute meningitis and cerebellar dysfunction complicating high-dose cytosine arabinoside therapy. Acta Med Scand 1986;220(5):493-5. PMID 3468760
181: Treves R, Gastine H, Richard A, et al. Aseptic meningitis and acute renal failure induced by ibuprofen during the treatment of systemic lupus erythematosus. [Article in French] Rev Rhum Mal Osteoartic 1983;50(1):75-6. PMID 6844855
182: Tuleja E, Bourgarit A, Abuaf N, Le Beller C, Séréni D. Rifampin-induced severe aseptic meningitis. Rev Med Interne 2010;31(9):e1-3. PMID 20674104
183: Tunkel AR, Starr K. Trimethoprim-sulfamethoxazole-associated aseptic meningitis. Am J Med 1990;88(6):696-7. PMID 2346166
184: Ulrich A, Weiler S, Weller M, Rordorf T, Tarnutzer AA. Cetuximab induced aseptic meningitis. J Clin Neurosci 2015;22(6):1061-3. PMID 25769257
185: Valk J. Aseptic meningitis after use of Amipaque. [Article in Dutch] Ned Tijdschr Geneeskd 1980;124(42):1788-9. PMID 7432569
186: van Asperdt JAA, De Moor RA. Aseptic meningitis, hepatitis and cholestasis induced by trimethoprim/sulfamethoxazole: a case report. BMC Pediatr 2021;21(1):345. PMID 34399711
187: van den Berg H, van der Flier M, van de Wetering MD. Cytarabine-induced aseptic meningitis. Leukemia 2001;15(4):697-9. PMID 11368387
188: Vanmelkebeke D, Madou R, Weekx S, Van Lint P, Jeurissen A. Follow the footprints to the diagnosis in a patient with meningismus. Clin Infect Dis 2010;50(11):1497. PMID 20433354
189: Vassalini P, Ajassa C, Di Ruscio V, et al. Aseptic meningitis induced by intravenous immunoglobulins in a child with acute Epstein-Barr virus infection and thrombocytopenia. Infez Med 2019;27(2):194-7. PMID 31205046
190: Velissaris D, Pintea M, Pantzaris N, et al. The role of procalcitonin in the diagnosis of meningitis: a literature review. J Clin Med 2018;7(6):148. PMID 29891780
191: Verstappen CCP, Heimans JJ, Hoekman K, Postma TJ. Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management. Drugs 2003;63(15):1549-63. PMID 12887262
192: Volle R, Nourrisson C, Mirand A, et al. Quantitative real-time RT-PCR assay for research studies on enterovirus infections in the central nervous system. J Virol Methods 2012;185(1):142-8. PMID 22766179
193: Voskens CJ, Goldinger SM, Loquai C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One 2013;8(1):e53745. PMID 23341990
194: Wallgren A. Une nouvelle maladie infectieuse du systeme nerveux central. Acta Pediatr Scand 1925;(4):158-82.
195: Wambulwa C, Bwayo S, Laiyemo AO, Lombardo F. Trimethoprim-sulfamethoxazole-induced aseptic meningitis. J Natl Med Assoc 2005;97(12):1725-8. PMID 16396068
196: Wang DY, Chong WS, Pan JY, Heng YK. First case report of aseptic meningitis induced by adalimumab administered for treatment of chronic plaque psoriasis. J Investig Allergol Clin Immunol 2017;27(3):183-5. PMID 28570223
197: Wasner CK. Ibuprofen, meningitis, and systemic lupus erythematosus. J Rheumatol 1978;5(2):162-4. PMID 671432
198: Weksler BB, Lehany AM. Naproxen-induced recurrent aseptic meningitis. DICP 1991;25(11):1183-4. PMID 1763533
199: Widener HL, Littman BH. Ibuprofen-induced meningitis in systemic lupus erythematosus. JAMA 1978;239(11):1062-4. PMID 304902
200: Wilde MI, Goa KL. Muromonab CD3: a reappraisal of its pharmacology and use as prophylaxis of solid organ transplant rejection. Drugs 1996;51(5):865-94. PMID 8861551
201: Willhite S, Juloori S. Chemical-induced aseptic meningitis as a result of intrathecal hydromorphone therapy: case report. Clin Case Rep 2021;9(8):e04599. PMID 34429991
202: Willmann O, Ahmad-Nejad P, Neumaier M, Hennerici MG, Fatar M. Toll-like receptor 3 immune deficiency may be causative for HSV-2-associated Mollaret meningitis. Eur Neurol 2010;63(4):249-51. PMID 20375513
203: Wright SE, Shaikh ZHA, Castillo-Lugo JA, Tanriover B. Aseptic meningitis and abducens nerve palsy as a serious side effect of high dose intravenous immunoglobulin used in a patient with renal transplantation. Transpl Infect Dis 2008;10(4):294-7. PMID 18086279
204: Xiao X, Zhang Y, Zhang L, Kang P, Ji N. The diagnostic value of cerebrospinal fluid lactate for post-neurosurgical bacterial meningitis: a meta-analysis. BMC Infect Dis 2016;16(1):483. PMID 27618955
205: Yelehe-Okouma M, Czmil-Garon J, Pape E, Petitpain N, Gillet P. Drug-induced aseptic meningitis: a mini-review. Fundam Clin Pharmacol 2018;32(3):252-60.** PMID 29364542
206: Zhang Y, Xiao X, Zhang J, Gao Z, Ji N, Zhang L. Diagnostic accuracy of routine blood examinations and CSF lactate level for post-neurosurgical bacterial meningitis. Int J Infect Dis 2017;59:50-4. PMID 28392319

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Drug-induced aseptic meningitis

Associated Disorders

Crohn disease
HIV infection
idiopathic thrombocytopenic purpura
rheumatoid arthritis
Sjogren syndrome
- systemic lupus erythematosus

Differential Diagnosis

bacterial meningitis
fungal meningitis
parasitic CNS infections
syphilitic meningitis
viral meningitis
- arbovirus
- enteroviruses
- herpes simplex virus 2 (HSV-2)
- HIV
- mumps virus
- respiratory viruses
- varicella zoster
- West Nile virus
- Behcet disease
- cerebral vasculitis
- Fabry disease
- granulomatosis with polyangiitis (Wegener granulomatosis)
- histiocytic necrotizing lymphadenitis (Kikuchi disease)
- leptomeningeal malignancy
- Mollaret meningitis
- rheumatological disorders
- adult-onset Still disease
- mixed connective tissue disease
- systemic lupus erythematosus
- sarcoidosis
- skull defects
- spontaneous intracranial hypotension
- Vogt-Koyanagi-Harada syndrome

Also Relevant

Drug-induced neurologic disorders
Headache associated with HIV and AIDS
Headache associated with intracranial infection
Medications and substances causing headache
Chemotherapy: neurologic complications
- Recurrent meningitis
- Viral meningitis

	• Primary prevention of drug-induced aseptic meningitis is generally not feasible due to the idiosyncratic nature of this adverse effect.
	• Secondary prevention involves the avoidance of drugs that previously produced drug-induced aseptic meningitis or that were suspected of causing drug-induced aseptic meningitis.

Drug-induced aseptic meningitis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Pathogenesis of drug-induced aseptic meningitis

Table 1. Selected Drugs, Chemicals, and Devices Associated with Drug-Induced Aseptic Meningitis

Antiepileptic drugs

Antineoplastics

Antibiotics

Monoclonal antibodies

Intravenous immunoglobulin

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Vaccines

Intrathecal drugs and diagnostics

Devices used for the treatment of neurologic disorders

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Table 2. Differential Diagnosis of Drug-Induced Aseptic Meningitis

Associated or underlying disorders

Diagnostic workup

Table 3. Comparison of CSF Results and Implications for Management and Outcome for the Physiological State, Bacterial Meningitis, Viral Meningitis, and Drug-Induced Aseptic Meningitis

Management

Outcomes

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

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