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 signs of meningitis, headache, neck stiffness, and fever, are the features of aseptic meningitis as well. Other symptoms include photophobia, myalgia, nausea, and vomiting. If aseptic meningitis is a part of a neurotoxic reaction to the drug, then there may be manifestations other than meningitis. In aseptic meningitis following vaccination, evidence exists of viral infection with associated signs, such as parotid swelling, as in the case of the measles-mumps-rubella vaccine. Convulsions may occur in some children and are probably associated with viral encephalitis.

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 (11). Controlled prospective studies are required to elucidate the neuropsychiatric complications of aseptic meningitis.

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, a protein content of 120 mg/dL, and 1120 polymorphonuclear leukocytes, of which 98% were polymorphonuclears. 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 or having the matter investigated. A diagnosis of ibuprofen-induced aseptic meningitis was made, and the patient was discharged to home with instructions to avoid taking ibuprofen.

Biological basis

	• Several drugs with differing pharmacodynamics are involved in the pathomechanism of aseptic meningitis.
	• Some therapeutic and diagnostic agents, administered intrathecally, can cause aseptic meningitis by direct action.

Etiology and pathogenesis

A list of drugs and chemicals reported to be associated with aseptic meningitis is shown in Table 1.

Table 1. Drugs, Chemicals, and Devices Associated with Aseptic Meningitis

Antiepileptic drugs
	• Carbamazepine • Lamotrigine (36)
Antimicrobial drugs
	• Sulfonamides
		- trimethoprim - trimethoprim/sulfamethoxazole - sulfasalazine
	• Cephalosporin • Ciprofloxacin • Fluoroquinolones: moxifloxacin • Isoniazid • Metronidazole • Ornidazole • Penicillin and its analogs
		- amoxicillin (33)
	• Rifampicin (39) • Antimicrosporidial
		- fumagillin (02)
	• Antivirals
		- valacyclovir
Antineoplastics (systemic use)
	• Cytosine arabinoside
Corticosteroids
	• Methylprednisolone acetate • Hydrocortisone sodium succinate
Monoclonal antibodies
	• Adalimumab (22; 44) • Cetuximab • Efalizumab • Infliximab • Muromonab CD-3* • Natalizumab (17)
Nonsteroidal antiinflammatory drugs
	• Celecoxib • Diclofenac • Ibuprofen • Naproxen • Sulindac • Tolmetin • Ketoprofen • Loxoprofen • Salicylates • Piroxicam • Rofecoxib (withdrawn from U.S. and other markets due to adverse effects)
Intraventricular drugs
	• Gentamicin • Antineoplastic drugs
Spinal intrathecal drugs
	• Antineoplastics
		- cytosine arabinoside - methotrexate
	• Antimicrobials • Baclofen • Steroids • Spinal anesthesia: bupivacaine (13)
Intrathecal diagnostic agents
	• Radiologic contrast media
		- iophendylate - metrizamide - iohexol
	• Radiolabeled albumin
Miscellaneous drugs
	• Allopurinol • Azathioprine • Famotidine • Intravenous immune globulin* (28) • Isotretinoin (09) • Leflunomide • Pyrazinamide • Ranitidine • Vaccines
		- polio - measles, mumps, and rubella - hepatitis B
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. Others are based on isolated case reports. For original sources of information, see the book titled Drug-induced Neurologic Disorders (21).

In a report from the French Pharmacovigilance Database, the most frequently involved drugs in drug-induced aseptic meningitis were intravenous polyvalent immunoglobulin, nonsteroidal antiinflammatory drugs, vaccines, and antimicrobials and it was not possible to differentiate them in terms of biological characteristics (07).

Antiepileptic drugs. Several case reports have linked antiepileptic drugs to aseptic meningitis. There are several case reports of carbamazepine-associated aseptic meningitis. In nearly 40% of cases in 1 case series, a positive rechallenge was reported in lamotrigine-associated aseptic meningitis and this should be considered in the differential diagnosis of culture-negative meningitis (37).

Antineoplastics. The usual manifestations of systemic antineoplastic neurotoxicity are cerebellar syndromes, leukoencephalopathy, and peripheral neuropathy. Aseptic meningitis has been reported after systemic treatment with cytosine arabinoside. It may be difficult to sort out some reports of meningitis associated with antineoplastic therapy because of occurrence of neoplastic meningitis.

Antibiotics. Systemic use of cephalosporins has been associated with cases of aseptic meningitis. Antibiotic-induced aseptic meningitis limits the direct application of antibiotics into the brain or subarachnoid space. An example is the use of colistin, an antibiotic that penetrates the brain poorly, for CNS infections due to multidrug-resistant Acinetobacter baumannii. Direct instillation of colistin into the CNS is an effective treatment in this situation but may cause chemical meningitis.

Diagnosis of drug-induced aseptic meningitis was difficult in a patient with human immunodeficiency virus who was receiving moxifloxacin as a modified treatment for tuberculosis following severe hepatotoxicity (34). Abnormal finding on CSF examination did not normalize to confirm diagnosis until risk was taken to withhold moxifloxacin.

Cetuximab. Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor, which is used for the treatment of cancer. There are isolated case reports of aseptic meningitis induced by cetuximab (29; 14; 40). The symptoms -- headache, neck stiffness, and high fever -- develop within a few hours of the first cetuximab administration. Diagnosis is established by CSF analysis, and recovery usually occurs within days to weeks after withdrawal of the drug.

Intravenous immunoglobulin. In recent years, intravenous immunoglobulin has been employed in the treatment of a variety of medical conditions such as idiopathic thrombocytopenic purpura, Guillain-Barré syndrome, dermatomyositis, and Kawasaki disease. Several cases of aseptic meningitis have been described. There are several published case reports of aseptic meningitis following intravenous immunoglobulin and these case reports can be easily retrieved from literature.

A retrospective review of all cases of IVIG-associated adverse transfusion reactions from 2008 to 2013 at a large tertiary care center identified 8 cases of aseptic meningitis representing an overall incidence of 0.60% for all treated patients and 0.067% for all IVIG infusions (06). Symptoms manifested within 24 to 48 hours of the infusion. The reactions were self-limited and resolved within 5 to 7 days, and treatment was supportive.

Muromonoab-CD3. This monoclonal murine IgG immunoglobulin is directed at the T3 receptors of the T-lymphocyte and is reportedly effective in the treatment of steroid-resistant kidney allograft rejection. Aseptic meningitis has been reported in patients following use of muromonoab-CD3 (orthoclone OKT3) in cardiac transplantation programs. Patients on this drug should be monitored for symptoms suggestive of meningeal irritation, and therapy should be discontinued if such symptoms develop.

Nonsteroidal antiinflammatory drugs (NSAIDs). These drugs have antiinflammatory, analgesic, and antipyretic properties, but can also produce adverse effects of which gastric ulceration and renal insufficiency are well known. CNS effects, such as aseptic meningitis, are less well known. Nine nonsteroidal antiinflammatory drugs have been implicated in causing drug-induced aseptic meningitis. This reaction appears to be unrelated to the chemical class of the nonsteroidal antiinflammatory drug or to the nonsteroidal antiinflammatory drug-mediated effects of the drug. There does not appear to be cross-reactivity of the nonsteroidal antiinflammatory drugs because, with a few exceptions, patients who develop aseptic meningitis after exposure to 1 nonsteroidal antiinflammatory drug have been previously and subsequently treated with other nonsteroidal antiinflammatory drugs without any reaction. Patients with systemic lupus erythematosus appear to be at greater risk for developing nonsteroidal antiinflammatory drug-induced aseptic meningitis.

Ibuprofen is the most frequently implicated drug in drug-induced aseptic meningitis. The most common background disease among these patients is systemic lupus erythematosus. Aseptic meningitis has been reported with other nonsteroidal antiinflammatory drugs including rofecoxib, which is reported to act by selectively inhibiting cyclooxygenase-2.

Trimethoprim-sulfamethoxazole. Aseptic meningitis is recognized as an adverse effect of administration of trimethoprim-sulfamethoxazole or trimethoprim-containing drugs. Known factors include autoimmune diseases and HIV infection. Pathomechanism is not well understood, although interleukin-6 has been implicated and rise of the level of this inflammatory cytokine in the blood as well as CSF may be a biomarker of trimethoprim-induced meningitis. Trimethoprim-sulfamethoxazole-induced aseptic meningitis used to be the most common form of antimicrobial therapy induced meningitis. Trimethoprim-sulfamethoxazole is not commonly used now and is primarily limited to Pneumocystis carinii pneumonia prophylaxis in AIDS patients; cases of drug-induced aseptic meningitis have been reported in these patients. A predominance of female patients and those with autoimmune diseases were reported in a review of 41 cases in the literature up to 2014 (08). Typical CSF findings included elevated white blood cell count with neutrophil predominance, elevated protein, and normal glucose. Full recovery was typical after discontinuation of the drug, but persistent paraplegia was reported in 1 case. Two further cases of trimethoprim-sulfamethoxazole-induced aseptic meningitis have been reported, and complete recovery occurred in both after discontinuation of the drug (23).

Intrathecal drugs and diagnostics. Aseptic meningitis is well documented for this route of administration. Some examples are as follows:

Antineoplastics. Neurotoxic effects of antineoplastic agents when administered systemically are well documented. The clinical manifestations of aseptic meningitis occur 2 to 4 hours after intrathecal injection of methotrexate. Meningismus is rarely seen after the first injection, but incidence increases with the number of intrathecal injections and is dose related. The presence of chemical preservatives in the solution for intrathecal injection may contribute to the meningeal reaction.

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

Antibiotics. Intrathecal aminoglycosides have been given without significant local reactions, although reports exist of neurotoxicity involving loss of hearing and polyradiculitis. There have been no reports of aseptic meningitis associated with intrathecal antibiotic use within recent years; the last published case was more than 25 years ago.

Corticosteroids. Intrathecal injections of methylprednisolone acetate are associated with aseptic meningitis. Epidural injections of steroids are considered safer, but cases of aseptic meningitis have been reported following this procedure as well. It is likely that in these cases, subarachnoid space was entered inadvertently.

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.

Intrathecal baclofen. Aseptic meningitis is a rare complication of intrathecal baclofen injections that must be recognized. It is a diagnosis of exclusion, and its pathophysiological mechanism remains unclear (05).

Leflunomide. This is a disease-modifying antirheumatic agent. Leflunomide has been reported as a cause of aseptic meningitis (25).

Radiologic contrast media. Arachnoiditis was recognized as a residual effect of oil-based intrathecal contrast agents used more than 2 decades ago. Introduction of water-soluble contrast agents reduced the incidence of aseptic meningitis, but it was still reported as a complication of metrizamide myelography in 5% of cases. Introduction of less toxic water-soluble agents further reduced adverse effects, but rare cases of aseptic meningitis are still reported after intrathecal iohexol injection for CT myelography. Neurotoxicity of radiological contrast media includes transient encephalopathy, seizures, and meningeal reactions.

Radiolabeled albumin. 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 might be implicated as causing an "allergic" reaction when injected into the subarachnoid space.

Intraventricular drugs. Aseptic meningitis is the most frequent complication of intraventricular chemotherapy for leptomeningeal metastases.

Devices used for treatment of neurologic disorders. Aseptic meningitis has been reported as a complication of hydrogel-coated coils used in the treatment of intracranial aneurysms.

Vaccines. Measles-mumps-rubella vaccines containing the Urabe strain of mumps were withdrawn in the United Kingdom in 1992 following demonstration of an increased risk of aseptic meningitis 15 to 35 days after vaccination. In 1998, a replacement measles-mumps-rubella vaccine called Priorix was introduced and the number of cases of aseptic meningitis decreased significantly. A systematic review of literature including clinical trials and other studies as well as case reports provides evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (12).

Pathomechanism of drug-induced aseptic meningitis. Although the exact pathomechanism of drug-induced aseptic meningitis is still unknown, the most commonly implicated drugs act more likely through immunological mechanisms. The proposed mechanisms of drug-induced aseptic meningitis fall into 2 categories: (1) hypersensitivity reactions and (2) direct irritation of the meninges. The latter usually involves direct instillation of an agent into the meninges. The circumstantial evidence in favor of a hypersensitivity reaction is the rapid development of symptoms following drug ingestion, the progressively shorter periods in recurrent cases, and the development of classic features (facial edema, conjunctivitis, pruritus) in some cases. Elevated levels of immune complexes in CSF of patients with drug-induced aseptic meningitis would support the hypersensitivity reaction theory. Some patients may be able to tolerate a drug initially but develop drug-induced aseptic meningitis on subsequent administration. One explanation is that the drug may behave as a hapten that binds to intravascular proteins, prompting the immune system of the body to subsequently recognize those proteins as foreign antigens.

Unlike the hypersensitivity reactions, drug-induced aseptic meningitis due to direct irritation may be delayed up to several weeks following the administration of the drug. The toxicity of the drug or the chemical in the CSF is related to the following criteria:

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

Predisposing factors. The following risk factors can be identified from studying drug-induced aseptic meningitis case reports:

• Patients suffering from autoimmune disorders may be at greater risk for developing drug-induced aseptic meningitis. • Patients with AIDS

Pathomechanism of aseptic meningitis induced by nonsteroidal antiinflammatory drugs (NSAIDS). Immune abnormalities such as serum and CSF antiribonucleoprotein antibodies may play a role in development of nonsteroidal antiinflammatory drug-induced aseptic meningitis in patients with a history of connective tissue disorders. Antiribonucleoprotein antibodies were positive in serum and CSF of a patient who developed aseptic meningitis following use of Loxoprofen, a nonsteroidal antiinflammatory drug (26). A drug lymphocyte stimulation test was negative, and symptoms resolved after cessation of Loxoprofen, confirming the diagnosis of nonsteroidal antiinflammatory drug-induced aseptic meningitis.

Pathomechanism of aseptic meningitis induced by intravenous immunoglobulin. The mechanism is not well understood, but the following hypotheses have been proposed:

	• Serum immunoglobulins, particularly IgG, can cross the blood-brain barrier. Breech of the blood-brain barrier in patients with autoimmune disorders of the CNS may allow entry of even the high molecular weight IgM into the CSF compartment. One of the cardinal features of Guillain-Barré syndrome is the high concentration of protein in the lumbar CSF. The endothelial barriers of the dorsal root ganglia and ventral roots, which already leak more than under normal conditions, become severely damaged and permit the passage of plasma proteins, including intravenous immunoglobulin.
	• The infused IgG is derived from a pool of multiple donors and is allogenic. Within the CSF, it may react with antigenic determinants on the endothelial cells of the meningeal vasculature, release cytokines, and lead to an inflammatory reaction as evidenced by the pleocytosis in the CSF.
	• Intravenous immunoglobulin-associated aseptic meningitis is presumed to be an acute hypersensitivity reaction limited to the leptomeninges without systemic anaphylaxis.
	• Patients with a history of migraine are more likely to develop aseptic meningitis when receiving the intravenous immune globulin, and this may be due to increased cerebrovascular sensitivity in migraineurs.

Pathogenesis of aseptic meningitis due to muromonab-CD3. First-dose reaction to muromonab-CD3 was originally considered to be idiosyncratic, but recurrence with subsequent administration is against this theory. Serum levels of various cytokines are elevated during this reaction). The pathomechanism remains uncertain.

Drug-induced eosinophilic meningitis. The pathomechanism is uncertain, but it is presumably an idiosyncratic reaction.

Epidemiology

• Exact figures are not available, but the overall incidence is 11 per 100,000 people per year in the United States.

No figures are available for overall incidence of drug-induced aseptic meningitis. The incidence of aseptic meningitis (including viral meningitis and other systemic disorders) has been reported as 11 per 100,000 person-years, compared with a rate of 8.6 per 100,000 for bacterial meningitis. Some idea of the frequency of occurrence of drug-induced aseptic meningitis can be obtained from cases reported with drugs in specific therapeutic areas.

Prevention

• Use of drugs known to induce aseptic meningitis in susceptible individuals should be avoided.

Prevention involves the avoidance of drugs suspected to produce aseptic meningitis in susceptible individuals. This is not always predictable because of the idiosyncratic nature of the adverse effects in some cases. The use of some drugs is unavoidable, even if there exists a risk of this complication. One example is the use of trimethoprim-sulfamethoxazole therapy for prophylaxis against Pneumocystis carinii in HIV-infected adults, even though AIDS is a risk factor for aseptic meningitis due to this drug.

Differential diagnosis

Confusing conditions

Differential diagnosis of drug-induced aseptic meningitis should be conducted according to the causes of aseptic meningitis (as shown in Table 2). The possibility that the patient may have recently taken an antibiotic and may have partially treated bacterial meningitis should also be considered.

Table 2. Differential Diagnosis of Drug-Induced Aseptic Meningitis

Aseptic meningitis of Mollaret Bacterial meningitis Cerebral vasculitis Fungal meningitis: eg, Cryptococcus neoformans Leptomeningeal cancer Neurosyphilis, early stage: aseptic meningitis Parasitic infections of the brain: Toxoplasma gondii and cysticercosis Histiocytic necrotizing lymphadenitis (Kikuchi disease) Viral meningitis
	• Arbovirus • Enteroviruses (Coxsackie and ECHO viruses) • Herpes simplex virus 2 • HIV • Mumps virus • Respiratory viruses (adenovirus, influenza virus, rhinovirus) • Varicella zoster • West Nile virus
Systemic diseases
	• Adult-onset Still disease, a systemic inflammatory disease (01) • Behçet disease • Fabry disease • Immunodeficiency states (eg, AIDS) • Mixed connective tissue disease • Sarcoidosis • Vogt-Koyanagi-Harada syndrome • Wegener granulomatosis
Defects at base of skull (eg, post-traumatic CSF fistula Iatrogenic)
	• Neurosurgical procedures • Intrathecal injections of drugs and diagnostic agents
Spontaneous intracranial hypotension syndrome (03)
Reproduced from: (21)

Aseptic meningitis neurosyphilis. Early neurosyphilis is usually characterized by asymptomatic meningitis, which is evidenced only by a cellular reaction in the CSF. However, it can be symptomatic, with headache and meningismus. Reactive serum and CSF-VDRL test results help in the diagnosis of aseptic meningitis neurosyphilis.

Histiocytic necrotizing lymphadenitis. Review of the literature has revealed that aseptic meningitis associated with Kikuchi disease was more likely to occur in men and was associated with a CSF/serum glucose ratio (35). Lymphadenopathy tended to occur simultaneously or after the onset of meningitis.

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

Drug-induced aseptic meningitis has an association with the following underlying disorders:

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

Diagnostic workup

	• Diagnosis of drug-induced aseptic meningitis is made on the basis of close association with a drug and exclusion of other causes of meningitis.
	• CSF examination is the most important laboratory test.
	• Blood biomarkers and MRI may provide important supplementary information.

Drug-induced aseptic meningitis cannot be distinguished from meningitis caused by other agents, and diagnosis is, therefore, based on close association between drug administration and onset of symptoms, as well as negative microbiology tests results (15). In a patient with headache, fever, meningeal signs, and CSF results consistent with meningitis, infections should be ruled out as a cause. Diagnosis of drug-induced aseptic meningitis is also made by exclusion, unless clear-cut evidence shows a relationship to the drug.

Laboratory investigations. White blood count and lumbar puncture are relevant tests.

	• The peripheral white blood count may be normal or elevated. A predominance of mononuclear cells in the CSF is characteristic of chronic recurrent meningitis.
	• Lumbar puncture usually reveals a high opening pressure. CSF examination shows pleocytosis ranging from a hundred to several thousand cells. The predominant cells are polymorphonuclears; however, rarely, lymphocytic and eosinophilic forms of drug-induced aseptic meningitis have also been reported. Eosinophils in the CSF are characteristic of aseptic meningitis associated with intravenous immunoglobulin.
	• CSF proteins are usually elevated. CSF culture results are always negative.
	• CSF lactic acid levels differentiate aseptic from early purulent meningitis. Drug-induced aseptic meningitis should be suspected in patients who have a normal CSF lactic acid level and a predominance of polymorphonuclear cells.

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 diagnosis of enterovirus infection from CSF samples as shown in research studies (42).

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 (31). 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.

In cases of nonsteroidal antiinflammatory drugs, meningitis mostly occurred within weeks of the start of therapy, but cases have been reported as late as 2 years after initiation of therapy. The CSF findings in these cases varied greatly. In general, there was polymorphonuclear pleocytosis, an elevation in protein concentration, and normal glucose content. Staining and culture of CSF for microorganisms were negative in all cases.

In postmyelographic meningitis, serum procalcitonin might be able to discriminate between bacterial and chemical causes of meningitis. Serum levels of procalcitonin, a precursor of calcitonin, are raised in bacterial meningitis due to leakage through the impaired blood-brain barrier, whereas they are normal in viral infections and other types of meningitis such as aseptic meningitis (41).

Magnetic resonance imaging. Pathologic meningeal enhancement has been reported in patients with bacterial and viral meningitis. MRI may show diffuse supratentorial white matter abnormalities that clear up after recovery from aseptic meningitis. MRI could be a valuable adjunct diagnostic procedure in drug-induced aseptic meningitis.

Management

• Discontinuation of the offending drug is the main step in management of drug-induced aseptic meningitis.

This depends on the drug involved and the condition of the patient. If drug-induced meningitis is suspected, the drug should be discontinued, if possible. Symptomatic treatment involves the use of antiemetics for nausea and analgesics for headache, taking care to avoid nonsteroidal antiinflammatory drugs suspected of inducing this condition. Headache due to drug-induced aseptic meningitis is different from headache due to overuse of analgesics as it may be relieved when the underlying cause is removed. Headache in drug-induced aseptic meningitis may have migrainous features, and there are single case reports of response to triptans (20).

Ibuprofen should not be prescribed for patients with systemic lupus erythematosus because of the frequent occurrence of ibuprofen-induced aseptic meningitis with the background of this disease.

A patient has reported to have developed drug-induced liver injury as well as meningitis while using ibuprofen (30). Both cleared up when the drug was discontinued.

Meningitis due to intravenous immunoglobulin. In the reported cases, aseptic meningitis appeared on the second or the third day of therapy, except in one case where the reaction appeared 2 days after the discontinuation of combined intravenous immunoglobulin and steroid therapy. A renal transplant recipient developed aseptic meningitis and diplopia due to abducens nerve palsy following intravenous immunoglobulin administration for antibody-mediated rejection (45). A patient with history of systemic lupus erythematosus, a well-known predisposing factor for aseptic meningitis due to other drugs, presented with meningismus 36 hours after first infusion of intravenous immunoglobulin (19). In most of the reported cases, intravenous immunoglobulin therapy was discontinued after onset of aseptic meningitis; however, in one case, intravenous immunoglobulin could not be discontinued because of the low platelet count and risk of life-threatening hemorrhage. Despite continuation of therapy in this case, the symptoms of meningitis cleared up on the fourth day of treatment with intravenous immunoglobulin. The following 3 measures are helpful in preventing or reducing the problems associated with high-dose intravenous immune globulin: (1) the initial infusion should be diluted and given slowly, and if well tolerated, then the concentration can be increased; (2) patients should be well hydrated during the treatment; and (3) antihistaminics and acetaminophen may be used as premedication.

Aseptic meningitis due to myelography. This is a hypersensitivity reaction to the contrast material, and patients usually recover after removal of the residual iophendylate and the administration of large doses of corticosteroids.

Outcomes

Recovery usually occurs following discontinuation of the offending drug.