Immunoglobulin-Induced Aseptic Meningitis in Juvenile Dermatomyositis: A Case Report

Aseptic meningitis is a known but unusual serious adverse effect of intravenous immunoglobulin (IVIG). It usually resembles infectious meningitis, which makes its diagnosis challenging. In this report, we present the case of a five-and-a-half-year-old Chinese girl with juvenile dermatomyositis (JDM) who presented with signs of meningismus 21 hours after the initiation of IVIG infusion. Her blood work at diagnosis showed neutrophilia and lymphopenia. The cerebrospinal fluid (CSF) analysis demonstrated neutrophilic pleocytosis, hyperproteinorrachia, and normoglycorrhachia. All microbiological tests were negative. The child fully recovered within 72 hours without neurological sequelae. IVIG-induced aseptic meningitis remains a diagnosis of exclusion. Although it is rare, pediatricians should be aware of this complication and avoid unnecessary investigations or treatment.


Introduction
Aseptic meningitis is a known severe adverse effect of immunoglobulin. It is rare and usually resembles infectious meningitis, which makes its diagnosis challenging. Its causes are either infectious or noninfectious (also called aseptic), consisting of autoimmune, neoplasia, and iatrogenic etiologies [1].
Intravenous immunoglobulin (IVIG) is widely used for a broad range of diseases, including immunodeficiencies, neuromuscular diseases, and autoimmune diseases. The treatment of juvenile dermatomyositis (JDM) with IVIG is generally considered effective as a second-line option, particularly for steroid-resistant patients or those with predominant skin activity [2][3][4]. A retrospective JDM cohort in 2011 demonstrated IVIG efficacy in controlling disease activity [5]. We discuss the case of a five-and-a-half-yearold girl with JDM, who experienced no adverse events with initial IVIG (Intragam P) administration, but subsequently developed aseptic meningitis after switching to another formulary IVIG (Privigen). The possible risk factors for developing aseptic meningitis are also discussed.
This article was previously posted to the ResearchSquare preprint server in November 2021.

Case Presentation
Our patient was a Chinese girl who initially presented with proximal muscle weakness and limping gait at four years of age. She also demonstrated dermatological features including heliotrope rash over the facial region and Gottron papules over her metacarpophalangeal and interphalangeal joints with cutaneous ulcerations. She had raised serum creatine kinase up to 3900 IU/L, and her MRI showed features of myositis over her bilateral shoulders, arms, and thigh muscles. She was given the diagnosis of JDM. Her Childhood Myositis Assessment Scale (CMAS) score (see the CMAS score sheet, Figure 1, in appendices) was 5/52 points ( Table 1).  The patient was initially treated with intravenous methylprednisolone, subcutaneous methotrexate, and six doses of monthly IVIG (Intragam P) at presentation. The IVIG was administered at a dosage of 1 gram/kg (total of 15 grams in the volume of 250 ml) over nine hours each day for two consecutive days. She had no adverse reaction to the medication. She responded well to treatment and her muscle power improved with a CMAS of 43 out of 52 four months later. Her steroid was gradually tapered down, but she developed worsening vasculitis with necrotic lesions and chondritis over both ears. Her skin condition remained refractory despite increasing the steroid and methotrexate dosage, as well as adding oral cyclosporin A. Cyclosporin A was subsequently switched to oral cyclophosphamide. Two days after the switch, IVIG was given additionally to optimize the control of her skin activity at the age of five-and-a-half years. Due to a change in our hospital drug formulary, the patient received Privigen instead. She was given 2 grams/kg (total of 32.5 grams in the volume of 325 ml), which was infused over 11 hours.
She was asymptomatic during the infusion but developed a high fever with a temperature of 40 ºC, headache, and repeated vomiting 10 hours after the completion of the injection. She also complained of neck pain and photophobia. There was no seizure, altered state of consciousness, or abnormal behavior. Physical examination demonstrated meningismus with neck stiffness and positive Kernig sign. There was no other focal neurological deficit.
Her blood tests ( Table 2) showed an elevated white cell count at 24 x 10 9 /L with neutrophilia (absolute neutrophil count: 17.3 x 10 9 /L), but normal C-reactive protein (<0.7 mg/L) and serum procalcitonin level (0.14 ng/ml). The CT of the brain was normal. The cerebrospinal fluid (CSF) was clear and colorless. Its analysis demonstrated neutrophilic pleocytosis with 2188 cells/mm 3 (87% neutrophils) without eosinophils, hyperproteinorrachia (0.66 g/L), and normoglycorrhachia (2.9 mmol/L in CSF and 4.7 mmol/L in plasma). She was initially treated with an intravenous meningitic dose of meropenem and acyclovir. Meropenem was chosen because of the abundance of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) in the Hong Kong community [6]. The cultures from her blood sample and CSF did not isolate any causative organisms.

Blood tests
White cell count 24 x 10 9 /L 5.0-15.0 x 10 9 /L Neutrophil count 17.3 x 10 9 /L 1.5-8.0 x 10 9 /L C-reactive protein <0.7 mg/L <5.0 mg/L Procalcitonin 0.14 ng/mL <0.5 ng/mL The blood culture showed no growth after 5 days of incubation  A lumbar puncture was repeated on day six and CSF analysis revealed a white cell count of 11 cells/mm 3 with 9% polymorphs, normal protein (0.19 g/L), and normal glucose levels (3.6 mmol/L in CSF and 5.3 mmol/L in plasma) ( Table 2). The patient completed a 14-day course of meropenem. Based on the temporal relation between IVIG administration and the symptoms onset, sterile cultures, as well as the normal Creactive protein and procalcitonin levels, a diagnosis of aseptic meningitis was made.
Her symptoms and fever subsided on day two of admission, and she recovered completely without any neurological sequelae.

Discussion
IVIG-induced aseptic meningitis is a rare complication, with an estimated incidence of 0.6-1% [7]. Apart from being used in the treatment of immune thrombocytopenia (ITP), IVIGs are also being given to patients as a treatment for various autoimmune and inflammatory diseases such as Kawasaki disease, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy. The exact pathophysiology of IVIGinduced aseptic meningitis remains unclear, with postulated mechanisms including direct toxic effect and immunological hypersensitive reaction [8].
Our patient did have the typical features of IVIG-associated aseptic meningitis described in the literature ( Table 3) [7,9]. Firstly, there was a temporal relationship between the onset of the symptoms of aseptic meningitis and high-dose IVIG therapy. Secondly, the symptoms and signs of meningismus quickly resolved within 48 hours in our patient. Thirdly, although the initial bloodwork revealed leukocytosis and neutrophilia, and the CSF analysis showed neutrophilic pleocytosis, all cultures were negative. All these fit into the picture of aseptic meningitis induced by IVIG as described by Bharath   Evidence concerning both patient and IVIG-related risk factors remains controversial. It has been suggested that a history of migraines, female sex, and underlying connective tissue disease such as systemic lupus erythematosus could be potential risk factors for developing aseptic meningitis following IVIG administration [10][11][12]. Further evidence is needed to evaluate whether JDM could also be a risk factor.
It is important to note that this was not the first time our patient had received IVIG. She developed aseptic meningitis after IVIG therapy was given at a higher dose (2 grams/kg) and faster rate (over 11 hours). Besides, our patient received a different brand of IVIG (Privigen) from her previous IVIG infusions (Intragam P) prior to the incidence of aseptic meningitis. Regarding IVIG-related risk factors, fast infusion rate and high initial dosage of IVIGs are thought to be risk factors for developing aseptic meningitis, but it is not always the case ( Table 4). There is no concrete evidence as to whether different IVIG brands have various potentials in causing aseptic meningitis. It was thought that IgA concentration might be related. The administration of IVIG containing IgA may cause dramatic clinical reactions in patients with serum anti-IgA [1,13]. The IgA contents in both Privigen and Intragam were not specified, with Privigen stating a maximum of 0.025 mg/ml and Intragam P reporting <0.025 mg/ml (   Supportive measures such as analgesics and antiemetics seem to be sufficient in these cases [30]. Corticosteroids do not seem to be effective in treating IVIG-induced aseptic meningitis [9,10,31]. Stiehm suggested that steroids or anti-TNF could be used in severe cases of aseptic meningitis [32]. However, in Kemmotsu et al.'s study, there were no differences in the clinical courses between patients who received no medical treatment and those treated with intravenous methylprednisolone [9]. Re-infusions are not contraindicated [7,27]. In case our patient requires IVIG in the future, Privigen will be avoided. Switching to subcutaneous preparation could potentially be an effective strategy in attenuating adverse effects [33]. Subcutaneous immunoglobulin (SCIG) was associated with lower rates of aseptic meningitis [10]. Several studies have shown that 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 antihistamine, could be considered [31].
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 IVIGinduced aseptic meningitis could be under-reported. Although there is increasing evidence on the selflimitedness of IVIG-induced aseptic meningitis and its temporal profile, the necessity for lumbar puncture and antibiotics remains controversial [7,34]. Given that our patient had been treated with several immunomodulatory medications and her increased risks for opportunistic infections, she was treated with intravenous antibiotics.

Conclusions
IVIG-induced aseptic meningitis remains a diagnosis of exclusion. Although it is rare, pediatricians should be aware of this complication and avoid unnecessary investigations or treatment. Supportive measures seem to be sufficient in these patients. Children usually recover without neurological sequelae.
submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.