Aseptic Meningitis Syndrome With Immunoglobulin Therapy

Aseptic meningitis syndrome (AMS) is a recognized but relatively rare adverse event associated with intravenous immunoglobulin (IVIG) therapy and less commonly with subcutaneous immunoglobulin (SCIG) therapy.^1,2

Although rare, AMS occurs in approximately 0.6% to 1% of patients receiving IVIG, with some studies reporting rates as high as 11%, depending on diagnostic criteria and patient population.^1,3 In a review of 151 published cases of drug-induced AMS, immunomodulators—including IVIG—were responsible for approximately 10% of cases, while nonsteroidal anti-inflammatory drugs (NSAIDs) were the most common cause, accounting for 33% of cases.⁴

IVIG and SCIG are FDA approved for treating several immune system disorders including immunodeficiency, autoimmune neuromuscular and rheumatologic conditions, and certain hematologic and inflammatory conditions.^2,5 Although immunoglobulin (Ig) therapy is generally safe and well tolerated, some patients experience complications, including AMS, which presents with symptoms resembling those of bacterial meningitis but without an identifiable infectious agent.⁶

Pathophysiology

The exact pathophysiology of AMS associated with IVIG and SCIG remains unclear, but several mechanisms have been proposed.¹ Potential molecular mechanisms of Ig therapy–induced AMS include:

• Hypersensitivity reactions (immune complex–mediated or cell-mediated) may affect the leptomeninges (the two innermost layers of the meninges [the arachnoid and pia mater] that cover and protect the brain and spinal cord).^5,7
• Direct meningeal irritation may be caused by Ig therapy components, primarily immunoglobulin G.^5,6
• Osmotic stress may transiently cross the blood–brain barrier, causing inflammation and cerebrospinal fluid (CSF) pleocytosis.⁶
• Inflammatory cytokines could be released (eg, interleukin-1 and monocyte chemoattractant protein-1), promoting neuroinflammation in predisposed individuals.⁶
• Eosinophilia has also been observed in the CSF of some Ig-treated patients, suggesting a hypersensitivity-related pathogenesis.³

Clinical Presentation

Symptoms of AMS typically appear within 24 to 48 hours after IVIG infusion and, less commonly, after SCIG.^6,8 Common clinical features include^5,6:

• severe headache;
• nuchal rigidity (neck stiffness);
• positive Kernig’s sign (severe stiffness of the hamstrings causing an inability to straighten the leg);
• photophobia (light sensitivity);
• nausea and vomiting;
• fever; and
• altered mental status (in severe cases).

A thorough diagnostic workup is important to rule out infectious causes such as bacterial meningitis.^1,8

Risk Factors

Several factors have been associated with an increased risk for developing AMS following IVIG or SCIG therapy^1,3,6,9:

• High-dose IVIG therapy (>1 g/kg)
• Rapid IVIG infusion rates
• History of migraines or previous AMS episodes
• Autoimmune diseases
• Dehydration
• Patient’s sex (potentially linked to hormonal or genetic predisposition)
• While some evidence suggests female sex as a potential risk factor, other data indicate a slight male predominance or no significant difference.^1,3,5,6

Differential Diagnosis

An AMS diagnosis is based on clinical history, laboratory findings, and imaging studies. Key diagnostic steps may include:

1. Lumbar puncture and CSF analysis. CSF findings typically reveal pleocytosis, elevated protein levels and normal glucose concentrations. Unlike bacterial meningitis, CSF cultures remain sterile.^1,3
2. Neuroimaging. Magnetic resonance imaging or computed tomography scans are performed to rule out other causes of meningeal irritation.^1,6,9
3. Laboratory tests. Inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate may be elevated but are nonspecific.^1,3,8,9
4. Clinical history. A temporal association between IVIG or SCIG administration and symptom onset is a critical diagnostic clue.^1,6,9

Mitigation Strategies

To reduce the risk for AMS recurrence in patients requiring continued Ig therapy, the following strategies may be employed:

• Use slower infusion rates to minimize osmotic stress on the blood–brain barrier.^3,6
• Add premedications, including acetaminophen, NSAIDs, corticosteroids, or antihistamines, to mitigate inflammatory responses.^3,6
• Include IV hydration.^1,6
• Administer the Ig dose over multiple days instead of a single high-dose administration.⁶
• Switch Ig brands, because some patients tolerate different brands better.^5,6
• Transition from IVIG to SCIG, particularly in patients with a history of migraine or recurring IVIG-related AMS.^1,6

Treatment of AMS

Acute AMS associated with Ig therapy is typically self-limiting and resolves within a few days after discontinuation of the infusion.^1,6 However, symptom management is essential to alleviate discomfort and prevent complications.⁶ The primary approach includes supportive care, symptomatic relief, and, in some cases, pharmacologic interventions. If AMS symptoms appear during IVIG infusion, stopping the infusion is recommended to prevent worsening of symptoms. If the prescriber determines that the IVIG infusion should be continued, or for subsequent infusions, restarting at the lowest practicable rate and only after symptoms have resolved, is prudent. Switching to a different IVIG brand or SCIG may be necessary for some patients.²

Pain management strategies focus on NSAIDs, such as ibuprofen or acetaminophen, to relieve severe headaches and nuchal rigidity, while opioids may be considered in severe cases but are generally avoided due to potential risks such as respiratory depression, reduced intestinal motility, altered mental status, and opioid dependance.^2,10 For associated symptoms, antiemetics such as ondansetron or metoclopramide can help alleviate nausea and vomiting, while antipyretics, including acetaminophen and NSAIDs, assist in managing fever.¹ Antihistamines, such as diphenhydramine or second-generation antihistamines like cetirizine, can be considered for patients with suspected allergic features or to help prevent recurrence in those with previous AMS episodes.^6,8 In severe or prolonged cases of AMS, corticosteroids, including IV methylprednisolone or oral prednisone, may be considered to reduce inflammation and hasten recovery, although their use remains case-dependent due to limited evidence.⁵

Hydration is an essential component of AMS risk mitigation, because the symptoms may be exacerbated by dehydration. Patients should be encouraged to drink adequate fluids, and IV hydration with normal saline may be necessary if oral intake is insufficient.³ Most AMS cases resolve within 24 to 72 hours with supportive care, but hospitalization may be necessary for patients with severe symptoms such as altered mental status, intractable vomiting, or uncontrolled headache. High-risk individuals, including those with autoimmune diseases or a history of complicated IVIG reactions, may require inpatient monitoring.¹ Acute medical attention or hospitalization may be required for patients who need pain management or IV hydration beyond what can be supported in an ambulatory setting.^1,3,6

Management Considerations For Pharmacists and Nurses

Pharmacists and nurses play critical roles in the prevention and management of AMS with IVIG and SCIG therapy.² The clinical team should take proactive steps to anticipate and mitigate AMS, including:

• Patient screening. Identify individuals at risk for AMS, such as those with a history of migraines or autoimmune diseases.
• Adjusting infusion rates and dosing schedules. Administer IVIG at slower rates and/or in divided doses to reduce the risk for adverse effects.
• Premedication protocols. Implement preventive measures, such as NSAIDs or corticosteroids, for high-risk patients.
• Educating patients. Provide information about AMS symptoms and advise seeking prompt medical attention if symptoms develop.
• Monitoring during infusion. Ensure early recognition of AMS symptoms for timely intervention.

Prognosis and Long-Term Considerations

Although most AMS cases are self-limiting and resolve without long-term complications, patients who require continued Ig therapy may experience recurrent episodes, necessitating risk mitigation strategies.^1,5,6 Clinicians should document previous AMS occurrences and adjust future Ig therapy accordingly to prevent recurrence.⁵

Conclusion

AMS is a recognized serious—albeit rare—complication of IVIG and SCIG therapy. It presents with symptoms mimicking bacterial meningitis, requiring careful diagnostic differentiation. The exact pathophysiology remains uncertain, with immune-mediated responses, osmotic effects, and cytokine release as proposed mechanisms. Identified risk factors include high-dose IVIG, rapid infusion rates, history of migraines, and prior AMS episodes. Diagnosis relies on clinical presentation, CSF analysis, and ruling out infectious causes. Management involves symptom relief, dosing and infusion rate modifications, and prophylactic strategies to reduce recurrence risk. Pharmacists and nurses are integral to patient education, individualized treatment optimization in accordance with the IgNS Standards of Practice,² and ensuring safe and effective immunoglobulin therapy for patients with AMS.

The authors reported no relevant financial disclosures.

References

1. Chan OM, et al. Cureus. 2022;14(11):e31808.
2. Immunoglobulin National Society. Immunoglobulin Therapy Standards of Practice. Edition 3.2. Published 2025. Accessed April 10, 2025. ig-ns.org/ standards-and-guides/
3. Jiang M, et al. Int Arch Allergy Immunol. 2023;184(6):513-528.
4. Kalmi G, et al. Therapie. 2020;75(6):605-615.
5. De Felice ELT, et al. Clin Rev Allergy Immunol. 2024;66(2):241-249.
6. Kretowska-Grunwald A, et al. J Clin Med. 2022;11(13):3571.
7. National Cancer Institute. NCI Dictionary of Cancer Terms. Accessed April 10, 2025. www.cancer.gov/ publications/ dictionaries/ cancer-terms/ def/ leptomeningeal
8. Russo CC, et al. Fed Pract. 2022;39(12):487-489.
9. Thouvenin L, et al. Ther Adv Drug Saf. Published Mar 29, 2021. doi:10.1177/20420986211004745
10. Regina AC, et al. Opioid toxicity. In: StatPearls [Internet]. StatPearls Publishing; 2025. Accessed April 14, 2025. www.ncbi.nlm.nih.gov/ books/ NBK470415/

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