Drug-Indiced Aseptic Meningitis:
Development of Subacute Sclerosing
Panencephalitis Following RepeatedIntraventricular Infusion Therapy with
Interferon Alpha/BetaGeorge Imataka, Eiji Nakagawa, Hideo
Yamanouchi & Osamu Arisaka

Cell Biochemistry and Biophysics
ISSN 1085-9195
Volume 61
Number 3
Cell Biochem Biophys (2011) 61:699-701
DOI 10.1007/s12013-011-9228-y

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Author's personal copy
Cell Biochem Biophys (2011) 61:699–701
DOI 10.1007/s12013-011-9228-y

TRANSLATIONAL BIOMEDICAL RESEARCH

Drug-Indiced Aseptic Meningitis: Development of Subacute
Sclerosing Panencephalitis Following Repeated IntraventricularInfusion Therapy with Interferon Alpha/BetaGeorge Imataka • Eiji Nakagawa •Hideo Yamanouchi • Osamu Arisaka

Published online: 12 July 2011
Ó Springer Science+Business Media, LLC 2011

Abstract Interferon (IFN)-a was reported to be effective
in longterm intrathecal treatment of subacute sclerosing
panencephalitis (SSPE). However, the side effects relatedwith longterm use of IFN-a/b are unclear. We evaluated thetherapeutic effects of IFN-a/b in a 13-years-old patient withSSPE. The cerebrospinal fluid (CSF) measles antibody titerwas 64 9 NT/1289HI, IgG-index was 4.5, and the SSPE
diagnosis was based on electroencephalography (Jabbourstage II on admission). With Inosiplex (INP) given orally,IFN-a (3 9 106 units) was infused intraventricularly twicea-week for 1-year. Resultantly, CSF cell count was elevated(2502/3), total protein and glucose levels were normal;
however, DIAM occurred repeatedly. Consequently,reduced IFN-a (5 9 105 units) with hydrocorton wasadministered at 2-months interval for 19 months, during
which, DIAM occurred four times. Therefore, IFN-b(3 9 106 units; twice-a-week) therapy was started andcontinued for 3 years. Although the symptoms wereimproved considerably, DIAM recurred after 15-months
therapy and CSF cell counts were also elevated (2121/3).
Since SSPE progressed to Jabbour-stage IV, indicated byirreversible consciousness disorder, IFN therapy was discontinued and INP monotherapy was followed for another

G. Imataka (&)  O. Arisaka
Department of Pediatrics, Dokkyo Medical University School ofMedicine, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japane-mail: geo@dokkyomed.ac.jp
E. NakagawaDepartment of Pediatric Neurology, National Center ofNeurology and Psychiatry, Musashi Hospital, Kodaira, JapanH. Yamanouchi
Department of Pediatrics, Saitama Medical University
School of Medicine, Saitama, Japan

3 years. We, therefore, concluded that the longterm intraventricular IFN-a/b infusion therapy of SSPE involved thepotential risk of DIAM with serious irreversible neurological sequelae and should be monitored carefully.

Introduction
Miyazaki et al. have reported a successful long-term
intrathecal treatment of subacute sclerosing panencephalitis (SSPE) with interferon (IFN) alpha [1]. As those authors
suggested, this drug may be effective and safe for SSPE.
The clinical course in which IFN prolonged survival will
give hope to many patients with SSPE.
We also performed intraventricular infusion therapy
with IFN in with SSPE. Short-term follow-up confirmed
improvement in the clinical symptoms. However, druginduced aseptic meningitis (DIAM) repeatedly occurred
even after 1 year since the start of this therapy, thereby
rapidly deteriorating the neurological symptoms. In thisarticle is reported the first case in which intraventricularinfusion therapy with IFN alpha/beta caused repeated
DIAM and this agent remained a serious neurologicalsequela. We describe the clinical course and discuss thisserious adverse effect with DIAM due to intraventricularinfusion therapy with IFN alpha/beta.

Case Report
The patient developed measles at 11 months of age. At
12 years and 10 months of age, failure of memory, personality changes, and myoclonic seizure appeared. The
cerebrospinal fluid (CSF) measles antibody titer was 649
in the NT method and 1289 in the HI method. The CSF123Author's personal copy
700

measles antibody titer was 169 in the two methods. WhenELISA was employed, the anti-IgG antibody titer was 640.0(cutoff value: 2.0). The patient was positive for CSF oligoclonal IgG band. The IgG index was 4.5. Electroencephalography revealed periodic synchronous discharge,suggesting SSPE (Fig. 1). On admission, the stage wasevaluated as Jabbour II. Inosiplex (INP) was orallyadministered, and intraspinal injection therapy with natural
human lymphoblast IFN-a (SumiferonÒ) at 3,000,000 units
was performed twice a week. After 1.5 months, Ommaya
reservoir was inserted to the ventricle, and intraventricularinfusion was started. After 1 year of treatment, DIAM
repeatedly occurred; fever was observed 12 h after IFN
administration. CSF from ventricular tap showed elevatedcell counts of 2,502/3. The total protein level was slightlyincreased. The glucose level was normal. Meningeal sings
improved in a few days. Subsequently, the dose of IFN-a
was decreased to 500,000 units, and combination therapy
with IFN-a and hydrocorton was administered at 2-monthintervals. However, DIAM recurred four times. After 1 year
and 7 months of treatment, the regimen was switched toIFN-b (BetaferonÒ) at 3,000,000 units, which was administered twice a week, because of recurrent DIAM. After
that, DIAM did not recur for 1 year and 3 months. After3 years of treatment, improvement in the symptoms facilitated drawing a picture (Fig. 2), reading characters, andsitting. However, 3 years and 4 months after onset, IFNb-related DIAM developed, with elevated cell counts of2,121/3 in CSF. Irreversible consciousness disorder rapidly
occurred, suggesting Jabbour stage IV. Then, IFN therapy
was discontinued, and single therapy with INP was continued for 3 years and now, the stage remains Jabbour IV.

Fp1
Fp2
F3F4C3C4P3P4O1O2F7F8T3T4T5T6E G

Fig. 1 Electroencephalography of the patient showed typical type ofperiodic synchronous discharge (arrows::)

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Cell Biochem Biophys (2011) 61:699–701

Fig. 2 She drawing the beautiful picture with word, number, human,animals, and flower with full of colors

Discussion
In 1978, Widener and Littman [2] indicated the developmentof DIAM after administration of ibuprofen to patients withsystemic lupus erythematosus. Since then, DIAM has beenreported to as a side effect in patients with autoimmune
disease. Non-steroidal anti-inflammatory agents, antibiotics,
vaccine, agents for intraspinal administration, and various
other agents caused DIAM [3]. Recently, massive dose of
immunoglobulin therapy has been administered to treat
primary immunodeficiency, Kawasaki disease, Guillain–
Barre syndrome, and idiopathic thrombocytopenic purpura,and the incidence of immunoglobulin-related DIAM has
increased [4]. The pathogenesis of DIAM remains to beclarified; however, drug administration rapidly caused
DIAM, but DIAM improved immediately after discontinuation. Therefore, the pathogenesis may involve hypersensitivity reaction related to the direct reactions of drugs andtype III allergic hypersensitivity response via the immune
mechanism. DIAM does not cause any specific symptoms
other than meningeal signs. However, DIAM develops
within 48 h after drug administration, and improves immediately after discontinuation. For continuous administration,
the interval until the symptom appears is shortened with thefrequency of dosing. For diagnosis, diagnosis by exclusion isperformed. Many studies have reported a good prognosis;
the symptom improves immediately after discontinuation,
without sequelae.
However, in our patient, DIAM repeatedly occurred,
resulting in severe sequelae, although we switched from
IFN-a to IFN-b. In the present patient, IFN was directly
administered into the ventricular pulp cavity via a reservoir
placed in the ventricle, suggesting that a direct stimulus
to the meninges induced DIAM. However, the immune

Author's personal copy
Cell Biochem Biophys (2011) 61:699–701

mechanism in the onset of DIAM remains to be clarified.
While administering long-term intraventricular infusion
therapy with IFN to patients with SSPE, the risk of DIAM,
which may lead to serious irreversible neurologicalsequelae as demonstrated in our patient, should beconsidered.

References

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infection alpha. Brain and Development, 27, 301–303.
2. Widener, H. L., & Littman, B. H. (1978). Ibuprofen-induced
aseptic meningitis in systemic lupus erythematosus. JAMA, 239,1062–1064.
3. Jolles, S., Sewell, W. A., & Leighton, C. (2000). Drug-induced
aseptic meningitis: Diagnosis and management. Drug Safety, 22,215–226.
4. Sekul, E. A., Cupler, E. J., & Dalakas, M. C. (1994). Asepticmeningitis associated with high-dose intravenous immunoglobulin
therapy: Frequency and risk factors. Annals of Internal Medicine,
121, 259–262.

1. Miyazaki, M., Nishimura, M., Toda, Y., Saijo, T., Mori, K., &Kuroda, Y. (2005). Long-term follow-up of a patient with subacute123