What is Drug-Induced Aseptic Meningitis (DIAM)?
Meningitis is an inflammatory condition of the meninges, the protective membranes covering the brain and spinal cord. It is typically caused by an infection, with viral infections being the most common cause of aseptic (non-bacterial) meningitis. However, a variety of medications can also trigger this inflammatory response, leading to a condition known as drug-induced aseptic meningitis (DIAM). DIAM is a diagnosis of exclusion, meaning it is considered only after infectious and other non-infectious causes have been ruled out. Symptoms often mirror infectious meningitis, making proper diagnosis challenging. The condition is rare and most cases see a rapid resolution of symptoms once the causative drug is discontinued.
Major Drug Classes Associated with DIAM
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
NSAIDs are one of the most frequently reported classes of medications to cause DIAM. Ibuprofen is the most commonly implicated NSAID, but others such as naproxen, diclofenac, sulindac, and ketoprofen have also been linked. The reaction can occur shortly after taking the drug, with symptoms typically resolving rapidly upon withdrawal. A notable risk factor is the presence of underlying autoimmune conditions, particularly systemic lupus erythematosus (SLE).
Antibiotics
A number of antibiotics, particularly sulfonamides and penicillins, are associated with DIAM. Trimethoprim-sulfamethoxazole (TMP-SMX) is the most common antibiotic cause, with cases predominantly reported in individuals who are immunocompromised or have underlying autoimmune diseases. Other antibiotics linked to DIAM include:
- Amoxicillin
- Ciprofloxacin and other fluoroquinolones
- Metronidazole
- Penicillin
- Isoniazid
- Rifampin
Intravenous Immunoglobulins (IVIG)
IVIG, a therapy used for a range of autoimmune and inflammatory conditions, is another documented cause of DIAM. In some reports, up to 1% of patients receiving IVIG may develop this adverse effect, though many reports find it to be rarer. High doses and a rapid infusion rate increase the risk. The reaction is thought to be a hypersensitivity response to the aggregated immunoglobulins. Symptoms most often manifest within 24 to 48 hours and resolve upon cessation of the infusion. A history of migraine may also increase susceptibility.
Monoclonal Antibodies and Other Immunomodulatory Drugs
Newer classes of drugs, including monoclonal antibodies, have also been implicated. Examples include infliximab, adalimumab, cetuximab, and muromonab-CD3. The mechanism is often linked to the release of cytokines, which trigger the inflammatory response. Other immunomodulatory drugs, like azathioprine, are also known causes.
Chemotherapeutic Agents
Certain cancer treatments can cause DIAM, particularly those administered intrathecally (into the spinal canal) or intraventricularly (into the ventricles of the brain). Examples include cytosine arabinoside and methotrexate. The direct exposure of the meninges to the drug can cause chemical irritation and inflammation.
Miscellaneous Drugs
A number of other medications and substances have been linked to DIAM in isolated case reports:
- Allopurinol: A medication for gout.
- Lamotrigine and Carbamazepine: Antiepileptic drugs.
- Ranitidine: A histamine-2 blocker.
- Vaccines: Certain vaccine formulations, particularly specific mumps strains no longer widely used, have been associated with aseptic meningitis.
- Intrathecal diagnostic agents: Such as contrast media used in radiology.
Risk Factors for DIAM
Several factors can increase an individual's susceptibility to DIAM:
- Autoimmune Diseases: Patients with autoimmune disorders, particularly systemic lupus erythematosus (SLE), are at a significantly higher risk for developing DIAM in response to medications like NSAIDs.
- Immunocompromised State: Individuals with weakened immune systems, such as those with HIV/AIDS, may be more vulnerable to certain drug-induced reactions, like those caused by TMP-SMX.
- Intrathecal Administration: Direct injection of drugs into the subarachnoid space carries a higher risk due to local chemical irritation.
- High Doses/Rapid Infusion: For IVIG, a higher dose and faster infusion rate are noted risk factors for aseptic meningitis.
- History of Migraine: Patients with a history of migraines may have increased cerebrovascular sensitivity, potentially predisposing them to IVIG-induced aseptic meningitis.
Clinical Presentation, Diagnosis, and Treatment
DIAM presents with symptoms that can be difficult to distinguish from infectious meningitis, including fever, headache, and a stiff neck (nuchal rigidity). Other signs like photophobia (light sensitivity), nausea, vomiting, myalgia (muscle aches), and altered mental status may also occur. Diagnosis involves a careful and comprehensive process of exclusion:
- Rule out Infection: A lumbar puncture (spinal tap) is performed to analyze cerebrospinal fluid (CSF). The fluid will show signs of inflammation (elevated white blood cells and protein) but will have negative bacterial cultures. Rapid PCR testing is often used to rule out viral causes.
- Evaluate Medical History: A thorough review of the patient's medication history is crucial to identify any recently started or changed drugs that are known to cause DIAM.
- Discontinuation and Resolution: The temporal association between drug exposure and symptom onset, combined with rapid clinical improvement after stopping the suspected medication, is key to the diagnosis.
Treatment is straightforward and involves immediate discontinuation of the offending drug. Symptoms typically resolve completely within 48 to 72 hours, though it can take longer. Supportive care may be necessary for symptomatic relief during this time. Re-exposure to the same drug is not recommended, as it can cause a recurrence of the meningitis.
Comparison Table: Drug-Induced Aseptic vs. Bacterial Meningitis
| Feature | Drug-Induced Aseptic Meningitis (DIAM) | Bacterial Meningitis |
|---|---|---|
| Etiology | Non-infectious inflammatory reaction caused by specific medications. | Bacterial infection of the meninges. |
| Onset of Symptoms | Can vary from minutes to weeks, often rapidly upon rechallenge. | Typically acute and more severe. |
| CSF Culture | Always negative for bacteria. | Positive for bacteria. |
| CSF Cell Profile | Elevated white blood cells, which can be lymphocytic or neutrophilic. | High white blood cell count with a predominance of neutrophils. |
| CSF Glucose | Usually normal, though sometimes mildly decreased. | Typically low. |
| CSF Protein | Often elevated. | Typically very elevated. |
| Prognosis | Generally excellent with full recovery after stopping the drug. | Potentially severe or fatal; risk of permanent neurological damage. |
Conclusion
Drug-induced aseptic meningitis is a rare but important diagnosis for clinicians to consider when faced with a patient exhibiting symptoms of meningitis. While infectious etiologies remain the primary concern, a comprehensive medication history is an essential part of the diagnostic workup. A wide range of drugs, from common NSAIDs and antibiotics to specialized chemotherapeutic and immunomodulatory agents, can trigger this non-infectious inflammatory response. The diagnosis is often confirmed by observing the resolution of symptoms after the suspected medication is withdrawn. Early identification and discontinuation of the causative drug are critical for a positive outcome and prevent unnecessary antibiotic use or further complications.
For more detailed information on a range of adverse drug reactions, visit MedLink Neurology, an authoritative resource for neurological conditions and their management.
