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  • Updated 08.17.2022
  • Released 06.30.1998
  • Expires For CME 08.17.2025

Drug-induced aseptic meningitis



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).

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