Drug-induced aseptic meningitis …

Douglas J Lanska MD MS MSPH

Neuropharmacology & Neurotherapeutics

Updated 04.29.2024
Released 06.30.1998
Expires For CME 04.29.2027

Drug-induced aseptic meningitis

Author: Douglas J Lanska MD MS MSPH

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Drug-induced aseptic meningitis

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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 (72; 147; 146; 157).

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 (202):

• 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) (37).

Mollaret meningitis, described by French neurologist Pierre Mollaret (1898–1987) in 1944, is a recurrent form of aseptic meningitis of unclear etiology (127). Bruyn and colleagues proposed the following criteria for Mollaret meningitis in 1962 (23; 66):

	• 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 (68; 122; 100; 30; 172). Some cases had presumptive noninfectious causes, such as systemic lupus erythematosus (122). In one case of so-called Mollaret meningitis, two of the five attacks were drug-induced (187). However, many cases of so-called Mollaret meningitis have been linked to herpes simplex virus type II (HSV-2) (13; 55; 106; 120; 176; 01; 80; 158; 196; 210; 71; 73), 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 (150), 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 (111). 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 (64). A patient receiving sulfamethoxazole developed aseptic meningitis that recurred with rechallenge after the patient had recovered from the initial exposure (16).

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 (39).

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.

Etiology and pathogenesis

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 (214).

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) (214). 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 (140)
Antineoplastics (systemic use)
	• Cytosine arabinoside
	• Zanubrutinib (a Bruton tyrosine kinase inhibitor used in B cell malignancy treatment) (213)
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 anti-inflammatory drugs*
	• Celecoxib • Diclofenac • Ibuprofen* • Ketoprofen • Loxoprofen • Naproxen (206) • Piroxicam • Rofecoxib (withdrawn from U.S. and other markets in 2004 due to adverse effects) • Salicylates • Sulindac • Tolmetin (169)
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) (50; 41) • Corticosteroids • Hydromorphone (209) • Monoclonal antibodies
		- Trastuzumab
Intrathecal diagnostic agents
	• Radiolabeled albumin • Radiologic contrast media
		- iophendylate - metrizamide - iohexol
Miscellaneous
	• Allopurinol (xanthine oxidase inhibitor, urate-lowering medication) (53; 77; 09) • Intravenous immune globulin* • Isotretinoin (vitamin A derivative) (26)
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 (130). 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 (130).

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 (20).

Antiepileptic drugs

Lamotrigine. Lamotrigine has been implicated as a cause of drug-induced aseptic meningitis (76; 179). 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 (179).

Carbamazepine. Carbamazepine has also been implicated as a cause of drug-induced aseptic meningitis (83; 180; 81; 40; 96).

Antineoplastics

Drug-induced aseptic meningitis has been reported after systemic treatment with cytosine arabinoside (177; 188; 27; 151; 195; 199; 109). 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 (191; 58; 163; 203; 92; 03; 56; 194; 04; 61; 149), and TMP-SMX is the most common antibiotic to cause drug-induced aseptic meningitis (22). 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 (22). 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 (07; 08).

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 (102).

Other. Drug-induced aseptic meningitis has been reported with multiple other systemic antibiotics, including cephalosporins (35; 137), fluoroquinolones (167), penicillin (163), amoxicillin (175; 159; 06; 31; 182; 60), rifampin (190), and fumagillin (12).

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 (136; 57; 192). 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 (117; 185; 78; 162; 164; 02; 25; 125; 116; 183; 208; 130), and many reports have considered these part of the cytokine release syndrome (46). Other adverse effects include leucopenia and severe infections.

Others. Additional reports of drug-induced aseptic meningitis with monoclonal antibodies have included adalimumab (89; 204), infliximab (95), ipilimumab (201), natalizumab (65), and intrathecal trastuzumab (67).

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 (174; 211; 133; 19; 197; 29; 104; 215).

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 (19). 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 (174), 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 (10), 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 (130). 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 (119).

Ibuprofen. Of the NSAIDs, ibuprofen has been most frequently implicated in drug-induced aseptic meningitis (107; 115; 121; 32; 79; 108; 141; 154; 165; 128; 99; 138; 45; 155; 132). Affected individuals may have repeated episodes with even small doses of ibuprofen (54). 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 (129; Mousavi Mirzae and Ahmadi 2021). Indeed, the most common background disease among these patients is systemic lupus erythematosus (181; 205; 207; 170; 178; 168; 189; 91; 70; 34; 82; 131; 63), but cases have also been reported in patients with mixed connective tissue disease (84; 99) and rheumatoid arthritis (86), for example, and in patients without connective tissue diseases (121).

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 (161; 94; 52; 38; 171; 103; 21; 152; 153). 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" (90; 43; 44). 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 (48). This was an update of an earlier Cochrane review published in 2020 on the same topic, which came to identical conclusions (47).

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 (124). 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 vaccine (123). 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 (184; 134; 148; 156). 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 (134). 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 (145). 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 (148). 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 (135). 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 (135).

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 (28). (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 (18). Epidural injections of steroids are considered safer, but cases of drug-induced aseptic meningitis have been reported following this procedure as well, perhaps by irritation of the meningeal layers from a medication used during the procedure or because the subarachnoid space was inadvertently entered (142).

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 (17).

Leflunomide. Leflunomide, a disease-modifying antirheumatic agent, has been reported as a cause of drug-induced aseptic meningitis (114).

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 (113) 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 (101; 193; 14; 69; 24; 42; 49). 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 (33; 166).

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 (88; 98; 51). Reported complications attributed to drug-induced aseptic meningitis in these patients include brain stem and cerebellar infarct (51) as well as delayed hydrocephalus (98).

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) (173)
	• Leptomeningeal malignancy
	• Mollaret meningitis*
	• Rheumatological disorders:
		- Adult-onset Still disease (05)
		- Mixed connective tissue disease
		- Systemic lupus erythematosus
	• Sarcoidosis
	• Skull defects (eg, post-traumatic CSF fistula; iatrogenic)
	• Spontaneous intracranial hypotension (15)
	• 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 (23; 66). 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 (186).

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 (165; 62; 214).

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 (214). 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 (165; 22). 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 (139).

The diagnosis of drug-induced aseptic meningitis requires that criteria for aseptic meningitis be met (186). 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 (214; 06) or polymorphonuclear (163; 130; 22; 97; 104), although uncommon eosinophilic forms of drug-induced aseptic meningitis may occur (163). 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 (163). 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 (75). In the past (1970s and early 1980s), multiple reports described CSF eosinophilia associated with oil-based, iodinated, intrathecal contrast agents (75). Aseptic eosinophilic meningitis has also been associated with IVIG (174; 204). 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 (160; 126; 11; 74; 75).

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 (200).

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 (144). 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 (87), although it has been most often studied in the clinical context of suspected post-neurosurgical bacterial meningitis (118; 110; 212; 216; 112; 105). 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) (36).

Serum and CSF levels of procalcitonin are elevated in bacterial meningitis, whereas they are normal in viral meningitis (198). 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 (59; 93; 76).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Douglas J Lanska MD MS MSPH

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
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Former Authors

K K Jain MD†

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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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

Etiology and pathogenesis

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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