IVIG-induced aseptic meningitis is a rare complication, with an estimated incidence of 0.6-1%.6,16 It was previously reported during the treatment for immune-mediated neurological disorders and neuromuscular diseases, which were mainly focused in the adult population. Reports on the pediatric population were relatively scarce. The exact pathophysiology of IVIG-induced aseptic meningitis remains unclear, with postulated mechanisms including direct toxic effect and immunological hypersensitive reaction.
Our patient did have the typical features of IVIG-associated aseptic meningitis described in the literature.6–7 First, there was a temporal relationship between the onset of the symptoms of aseptic meningitis and the high dose IVIG therapy. Secondly, the symptoms and signs of meningismus quickly resolved within 48 hours in our patient. Thirdly, although the initial blood-work revealed leukocytosis, neutrophilia, and the CSF analysis showed neutrophilic pleocytosis but all cultures were negative. These all fit into the picture of aseptic meningitis induced by IVIG described by Bharath and Kemmotsu.
Evidences concerning both patient and IVIG-related risk factors remain controversial. It had been suggested that history of migraines, female sex and underlying connective tissue disease such as systemic lupus erythromatosus could be potential risk factors for developing aseptic meningitis after IVIG.13,14,15 Further evidences are needed to evaluate whether juvenile dermatomyositis could be a risk factor.
It is important to note that this was not the first time our patient had IVIG. She developed aseptic meningitis after having IVIG therapy given at a higher dose (2gram/kg) and faster rate (over 11hours). Besides, our patient received a different brand of IVIG PrivigenTM from her previous IVIG infusions Intragam PTM prior to her incidence of aseptic meningitis. In regard to IVIG-related risk factors, particularly the dosage and the infusion rate, evidence remains disputable.8,13 We do not know why some IVIG brands seem to be more likely to cause aseptic meningitis. It was thought that it could possibly be related to the IgA concentration given that the administration of IVIG containing IgA may cause dramatic clinical reactions in patients with serum anti-IgA.1,21 The IgA content in PrivigenTM was 0.025mg/ml which is slightly higher than that of Intragam PTM, <0.025mg/ml (Table 1). Although in Bharath’s retrospective study, 50% patients developed aseptic meningitis after PrivigenTM infusion, due to the small number of patients, the brands of IVIG or varying commercial preparations has not been identified as a risk factor.
Table 1
Compositions of PrivigenTM and Intragam PTM.
| PrivigenTM | Intragam PTM |
IgG 1 | 67.8% | 61% |
lgG2 | 28.7% | 36% |
lgG3 | 2.3% | 3% |
lgG 4 | 1.2% | 1% |
lgA | 0.025mg/ml | <0.025mg/ml |
Excipients | L-proline, WFI | Maltose 10mg/ml |
Supportive measures such as analgesics and anti-emetics seem to be sufficient. Corticosteroids do not seem to be effective in treating IVIG-induced aseptic meningitis.7,12,13 Re-infusions are not contraindicated.6,16 In case our patient requires IVIG in the future, PrivigenTM will be avoided. Switching to subcutaneous preparation could potentially be an effective strategy in attenuating adverse effects.19 Subcutaneous immunoglobulin (SCIG) was associated with lower rates of aseptic meningitis.20 There are increasing number of studies show that subcutaneous immunoglobulin (SCIG) can be used in treating various diseases including immunodeficiency diseases, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy etc. Further research is needed to determine its efficiency as an immunomodulatory therapy. Preventive measures including infusing at a slow rate, pre-hydration and adequate fluid intake throughout infusion, as well as premedication with acetaminophen and anti-histamine could be considered.12
Milder cases of aseptic meningitis might not necessarily be recognized, given that aseptic meningitis is such a rare complication of IVIG. On the other hand, post-IVIG headache is common. The true Incidence of IVIG-induced aseptic meningitis could be under-reported. Although there is increasing evidence on the self-limitedness of IVIG-induced aseptic meningitis and its temporal profile, the necessity for lumbar puncture and antibiotics remains controversial.6,17,18 Given that our patient had been treated with several immunomodulatory medications and her increased risks of opportunistic infections, she was treated with intravenous antibiotics.