Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev
Short communication
Anti-aquaporin 4 antibody-positive acute disseminated encephalomyelitis Akihisa Okumura a,b,⇑, Mika Nakazawa a, Ayuko Igarashi a, Shinpei Abe a, Mitsuru Ikeno a, Eri Nakahara a, Yuichiro Yamashiro c, Toshiaki Shimizu a, Toshiyuki Takahashi d a
Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan b Department of Pediatrics, Aichi Medical University, Nagakute, Aichi, Japan c Probiotics Research Laboratory, Juntendo University Graduate School of Medicine, Tokyo, Japan d Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan Received 4 February 2014; received in revised form 29 April 2014; accepted 30 April 2014
Abstract Objective: To describe the clinical and neuroimaging features of a young female patient with acute disseminated encephalomyelitis associated with anti-aquaporin-4 antibodies. Methods: The patient had mild encephalopathy 14 days after influenza vaccination. Cerebrospinal fluid analysis revealed an increased cell count and a marked increase in myelin basic protein. Magnetic resonance imaging (MRI) demonstrated multiple lesions in the juxtacortical white matter. The patient was diagnosed with acute disseminated encephalomyelitis and treated with methylprednisolone pulse therapy. She recovered in 1 month. However, right retrobulbar optic neuritis appeared 2 months after discharge, and serum anti-aquaporin 4 antibodies were measured with a cell-based assay. Results: Anti-aquaporin 4 antibodies were present in the patient’s serum. She was treated with a prolonged course of oral prednisolone. The patient was negative for serum anti-aquaporin 4 antibodies 8 months after the second clinical event, and prednisolone was discontinued 13 months after the second clinical event. Serum anti-aquaporin 4 antibodies remained negative 4 months after the discontinuation of prednisolone. There was no evidence of relapse at 9 months after discontinuation of steroids. Conclusions: This case will expand the spectrum of anti-aquaporin-4 antibody-related central nervous system disorders. The measurement of anti-aquaporin 4 antibody may be considered in patients with a clinical diagnosis of acute disseminated encephalomyelitis and a second clinical event within a short interval. Ó 2014 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Keywords: Anti-aquaporin 4 antibody; Acute disseminated encephalomyelitis; Optic neuritis; Steroids; Vaccination
1. Introduction
⇑ Corresponding author at: Department of Pediatrics, Aichi Medical
University, 1-1 Yazako Karimata, Nagakute, Aichi 480-1195, Japan. Tel.: +81 561 62 3311; fax: +81 561 63 4835. E-mail address: [email protected] (A. Okumura).
Neuromyelitis optica (NMO), the coexistence of optic neuritis with myelitis, was recognized in the 19th century and had long been considered a variant of multiple sclerosis (MS) [1]. In 2004, Lennon et al. reported the presence of a circulating IgG autoantibody specific to
http://dx.doi.org/10.1016/j.braindev.2014.04.013 0387-7604/Ó 2014 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Please cite this article in press as: Okumura A et al. Anti-aquaporin 4 antibody-positive acute disseminated encephalomyelitis. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.04.013
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A. Okumura et al. / Brain & Development xxx (2014) xxx–xxx
NMO [2]. The astrocyte water channel protein aquaporin 4 (AQP4) was identified as the target of NMO autoantibodies [3]. At present, anti-AQP4 antibody-positive NMO is distinguished as a clinical entity independent from MS [4]. Thus, serological identification of antiAQP4 antibodies is currently included as an additional diagnostic criterion for NMO [5]. Optic neuritis and/or spinal cord lesions are frequent clinical manifestations of anti-AQP4-mediated central nervous system (CNS) disorders. However, the spectrum of anti-AQP4-mediated CNS disorders has not been sufficiently elucidated, especially in children. We encountered a young female patient with acute disseminated encephalomyelitis (ADEM) in whom anti-AQP4 antibodies were detected. Here, we report the clinical course and neuroimaging findings of this patient. 2. Patient report A previously healthy 4-years-old female was admitted to our hospital due to reduced consciousness and difficulty ambulating. She was the first child of nonconsanguineous healthy parents. Her past and family histories were unremarkable, and her psychomotor development was within normal limits. She received an influenza vaccine containing the A/California/7/2009 (H1N1) pdm09, A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 strains 14 days before the onset of neurological symptoms. Three days before admission, somnolence and behavioral changes such as irritability were observed in association with a low-grade fever of approximately 38 °C. Meningitis was suspected because she had nuchal rigidity. On admission, her body temperature was 37.0 °C, heart rate was 96 beats per minute, respiration rate was 24 per minute, and blood pressure was 98/58 mmHg. She was oriented but mildly somnolent. Physical examination was remarkable for nuchal rigidity, and neurological examination demonstrated hyperreflexia in both legs. Cerebrospinal fluid (CSF) analysis revealed an elevated cell count of 109 cells/ll, with normal protein and glucose levels. Laboratory data were otherwise unremarkable. A marked increase (>2000 pg/ ml) in myelin basic protein was found in the CSF on admission; no measurement of oligoclonal bands and glial fibrillary acidic protein was performed. Virological studies were negative for influenza virus (rapid antigen test), cytomegalovirus (enzyme-linked immunosorbent assay), herpes simplex virus (enzyme-linked immunosorbent assay), and Epstein–Barr virus (enzyme-linked immunosorbent assay). Electroencephalogram showed mild slowing of background activity. Cranial magnetic resonance imaging (MRI) demonstrated multiple high-intensity areas in the juxtacortical white matter on T2-weighted imaging and fluid-attenuated inversion recovery (Fig. 1). No lesions were found in the corpus
callosum, periventricular white matter, or deep gray matter, including the hypothalamus, cerebellum, brainstem, and cervical spinal cord. No abnormalities were recognized on funduscopic examination. The patient was diagnosed with ADEM and treated with methylprednisolone pulse therapy, intravenous acyclovir, and mannitol. Her somnolence resolved on the third day of admission, and neurological abnormalities resolved on the ninth day of admission. An enhance MRI on the tenth day of admission revealed a reduction in brain lesions and no contrast enhancement (Fig. 1). Oral prednisolone was prescribed at a dose of 1 mg/kg/ day for 1 week, followed by 0.5 mg/kg/day for 2 weeks. The patient was discharged from our hospital on day 13. An MRI at 1 month after the onset of the first clinical event showed that the cerebral lesions had disappeared (Fig. 1). Two months after discharge, the patient’s mother noticed disconjugate eye movements. Ophthalmological examination revealed retrobulbar optic neuritis of the right eye. MRI demonstrated swelling and increased intensity in the proximal portion of the right optic nerve on T2-weighed imaging (Fig. 1) but no brain or spinal lesions. The patient was again treated with methylprednisolone pulse therapy. The right optic nerve lesion resolved 9 days after the initiation of methylprednisolone pulse therapy (Fig. 1). Serum anti-AQP4 antibodies were detected in the patient’s serum during the second clinical event using cell-based assays [6]. Once anti-AQP4 antibodies were detected, the patient was prescribed a prolonged course of oral prednisolone with a gradual taper. After methylprednisolone pulse therapy, 2 mg/kg/day of prednisolone was given for 1 week. The dose of prednisolone was then reduced every 1–2 months. The patient tested negative for serum anti-AQP4 antibodies 8 months after the second clinical event. Prednisolone was discontinued 13 months after the second clinical event. The patient’s serum again tested negative for anti-AQP4 antibodies 4 months after the discontinuation of prednisolone. There was no evidence of relapse at 9 months after the discontinuation of steroids. The patient’s psychomotor development and growth were normal at the last follow-up at 79 months of age. 3. Discussion Our patient initially presented with the typical features of ADEM, which was followed by optic neuritis after the discontinuation of steroids. Serum anti-AQP4 antibodies were present during the acute period and disappeared after long-term treatment with oral steroids. This case will expand the spectrum of anti-AQP4 antibody-related CNS disorders. A revised consensus definition of ADEM was proposed by the International Pediatric Multiple Sclerosis
Please cite this article in press as: Okumura A et al. Anti-aquaporin 4 antibody-positive acute disseminated encephalomyelitis. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.04.013
A. Okumura et al. / Brain & Development xxx (2014) xxx–xxx
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Fig. 1. MRI findings. Top. Cerebral lesions during the first clinical event (fluid-attenuated inversion recovery). Left. Multiple high-intensity areas were seen in the juxtacortical cortical white matter. Middle. Cerebral lesions became less clear on the tenth day of admission. Right. No lesions were seen 1 month after onset. Bottom. Right optic nerve lesion during the second clinical event. Left. T2-weighted images at the onset of the second clinical event. Swelling and increased intensity (arrow) were observed in the proximal portion of the right optic nerve. Right. T2-weighted images 9 days later. Swelling and increased intensity were resolved (arrow).
Study Group in 2012 [7]. The clinical manifestation and neuroimaging features of our patients almost completely met this definition. The consensus definition makes mandatory the presence of encephalopathic symptoms, such as behavioral changes and an altered level of consciousness. Our patient had behavioral changes and a decreased level of consciousness at the onset of symptoms. MRI showed bilateral, asymmetrical, poorly demarcated areas of increased signal intensity in the juxtacortical white matter on T2-weighted imaging. No T1-hypointense lesions were present in the white matter. Although the size of the cerebral white matter lesions was relatively small, the neuroimaging features of our patient were largely compatible with the ADEM consensus definition. ADEM is a very rare initial manifestation of an antiAQP4 antibody-mediated brain disorder. McKeon et al. reported the clinical manifestation of anti-AQP4 antibodies in children [8]. The initial clinical presentation in 58 subjects included optic neuritis in 31 (53%), transverse myelitis in 13 (22%), optic neuritis and transverse myelitis in five (9%), and brain symptomatology in nine (16%). Although encephalopathy was seen in three of nine children presenting with brain symptomatology,
none of them was diagnosed with ADEM. HinoFukuyo et al. reported the clinical features of 18 children with anti-AQP4 antibodies in Japan [9]. Sixteen (94%) of 18 subjects had optic neuritis and/or transverse myelitis, and none had ADEM. Long et al. measured the seroprevalence of anti-AQP4 antibodies in 200 Chinese patients with several types of acute demyelinating disorders [10]. Two patients with ADEM were included, and both tested negative for anti-AQP4 antibodies. Saiki et al. reported the case of a 36-years-old woman with anti-AQP4 antibody-positive NMO associated with ADEM-like asymmetric tumefactive hyperintense lesions in the subcortical white matter after Mycoplasma pneumoniae infection [11]. These reports suggest that ADEM is an unusual manifestation of anti-AQP4 antibody-mediated brain disorders. In our patient, the interval between the first clinical encephalopathy event with multifocal cerebral lesions and the second event with right optic neuritis was 2 months. According to the consensus ADEM definition, these clinical events are operationally considered to represent a single acute event [7]. It is difficult to determine whether anti-AQP4 antibodies were present during the first encephalopathy event. If the two clinical
Please cite this article in press as: Okumura A et al. Anti-aquaporin 4 antibody-positive acute disseminated encephalomyelitis. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.04.013
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events represented a single acute event, anti-AQP4 antibodies would be related to both events. Another possibility is that anti-AQP4 antibodies were induced by the first event. If this is the case, the anti-AQP4 antibodies were only related to the second event with optic neuritis. Optic neuritis without additional brain lesions is a common manifestation of anti-AQP4 antibody-mediated brain disorders. In the series reported by McKeon et al., 31 of 58 children with anti-AQP4 antibodies had optic neuritis alone [8]. AQP4 is highly expressed on astrocyte end feet in the periependymal area including the optic nerves, spinal cord, peri-fourth ventricular and periaqueductal gray regions, hypothalamus, and brainstem. Thus, the optic nerve can be a target of anti-AQP4 antibody-mediated CNS disorders. In contrast, the role of anti-AQP4 antibodies in juxtacortical white matter lesions is insufficiently understood. The distribution of brain lesions cannot be explained by areas of high AQP4 expression. It is noteworthy that white matter lesions resembling ADEM or large tumefactive lesions have been infrequently reported in children with anti-AQP4 antibody-mediated CNS disorders, although pathogenesis of white matter lesions remains unknown [11,12]. It is important to note that patients with the anti-AQP4 antibody are at increased risk of progressive disability without appropriate treatment. The relationship between anti-AQP4 antibodies and white matter lesions is an important subject for future study. The relationship between influenza vaccination and the development of ADEM must be cautiously interpreted. Previous studies found that 5–12% of patients with ADEM had a history of vaccination within a month of presentation [13,14]. Several reports have noted ADEM after influenza vaccination, including reports from Japan [15,16]. However, no causal relationship between ADEM and influenza vaccination has been proven epidemiologically or pathologically. It is difficult to determine whether the influenza vaccine was the cause of ADEM in our patient. The treatment regimen of our patient was not easy to determine. Although there is no standard treatment regimen for ADEM, methylprednisolone pulse therapy followed by an oral steroid taper over 4–6 weeks is the most common treatment [17]. In contrast, long-term immunosuppressive treatment including azathioprine and rituximab is suggested once the diagnosis of NMO has been confirmed because NMO frequently shows a relapsing course, with incomplete recovery and worsening of neurological deficits [1]. Our patient responded well to steroids, although the second clinical event with neurological symptoms was seen after the discontinuation of steroids. Thus, slow tapering of oral steroids over 12 months was prescribed to treat the second event. The decision to discontinue steroids in our patient was made after the absence of anti-AQP4 antibodies was confirmed. Monitoring of anti-AQP4 antibodies may
be useful in determining whether treatment should be stopped. However, the possibility of recurrence remains. A long-term follow-up study found that the inter-attack interval ranged from 7 to 137 months [18]. In summary, we report the case of a young female with ADEM and typical clinical manifestations associated with anti-AQP4 antibody. Long-term steroid treatment was effective, with no residual neurological deficits and the disappearance of anti-AQP4 antibodies. Measurement of anti-AQP4 antibodies may be considered in patients with a clinical diagnosis of ADEM who have a second event after a short interval.
Acknowledgments We thank the patient and her families for their cooperation. This study is supported by the Grants from the Ministry of Health, Labor, and Welfare of Japan (H24Shinkou-Ippan-002 and H25-Nanji-Ippan-009), and the Grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (23591518). References [1] Trebst C, Jarius S, Berthele A, Paul F, Schippling S, Wildemann B, et al. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 2014;261:1–16. [2] Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004;364:2106–12. [3] Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005;202:473–7. [4] Jarius S, Wildemann B. AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 2010;6:383–92. [5] Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485–9. [6] Takahashi T, Fujihara K, Nakashima I, Misu T, Miyazawa I, Nakamura M, et al. Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 2007;130:1235–43. [7] Krupp LB, Tardieu M, Amato MP, Banwell B, Chitnis T, Dale RC, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler 2013;19:1261–7. [8] McKeon A, Lennon VA, Lotze T, Tenenbaum S, Ness JM, Rensel M, et al. CNS aquaporin-4 autoimmunity in children. Neurology 2008;71:93–100. [9] Hino-Fukuyo N, Takahashi T, Haginoya K, Uematsu M, Tsuchiya S, Fujihara K. Clinical features of Japanese pediatric patients with anti-aquaporin 4 antibody (In Japanese). No To Hattatsu 2011;43:359–65. [10] Long Y, Qiu W, Hu X, Peng F, Lu Z, Wang Y, et al. Antiaquaporin-4 antibody in Chinese patients with central nervous system inflammatory demyelinating disorders. Clin Neurol Neurosurg 2012;114:1131–4.
Please cite this article in press as: Okumura A et al. Anti-aquaporin 4 antibody-positive acute disseminated encephalomyelitis. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.04.013
A. Okumura et al. / Brain & Development xxx (2014) xxx–xxx [11] Saiki S, Ueno Y, Moritani T, Sato T, Sekine T, Kawajiri S, et al. Extensive hemispheric lesions with radiological evidence of blood–brain barrier integrity in a patient with neuromyelitis optica. J Neurol Sci 2009;284:217–9. [12] Lotze TE, Northrop JL, Hutton GJ, Ross B, Schiffman JS, Hunter JV. Spectrum of pediatric neuromyelitis optica. Pediatrics 2008;122:e1039–47. [13] Leake JA, Albani S, Kao AS, Senac MO, Billman GF, Nespeca MP, et al. Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr Infect Dis J 2004;23:756–64. [14] Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. Neurology 2002;59:1224–31.
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[15] Lapphra K, Huh L, Scheifele DW. Adverse neurologic reactions after both doses of pandemic H1N1 influenza vaccine with optic neuritis and demyelination. Pediatr Infect Dis J 2011;30:84–6. [16] Fujii K, Suyama M, Chiba K, Okunushi T, Oikawa J, Kohno Y. Acute disseminated encephalomyelitis following 2009 H1N1 influenza vaccine. Pediatr. Int. 2012;54:539–41. [17] Marin SE, Callen DJ. The magnetic resonance imaging appearance of monophasic acute disseminated encephalomyelitis: an update post application of the 2007 consensus criteria. Neuroimaging Clin N Am 2013;23:245–66. [18] Collongues N, Marignier R, Ze´phir H, Papeix C, Fontaine B, Blanc F, et al. Long-term follow-up of neuromyelitis optica with a pediatric onset. Neurology 2010;75:1084–8.
Please cite this article in press as: Okumura A et al. Anti-aquaporin 4 antibody-positive acute disseminated encephalomyelitis. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.04.013
Short communication
Anti-aquaporin 4 antibody-positive acute disseminated encephalomyelitis Akihisa Okumura a,b,⇑, Mika Nakazawa a, Ayuko Igarashi a, Shinpei Abe a, Mitsuru Ikeno a, Eri Nakahara a, Yuichiro Yamashiro c, Toshiaki Shimizu a, Toshiyuki Takahashi d a
Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan b Department of Pediatrics, Aichi Medical University, Nagakute, Aichi, Japan c Probiotics Research Laboratory, Juntendo University Graduate School of Medicine, Tokyo, Japan d Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan Received 4 February 2014; received in revised form 29 April 2014; accepted 30 April 2014
Abstract Objective: To describe the clinical and neuroimaging features of a young female patient with acute disseminated encephalomyelitis associated with anti-aquaporin-4 antibodies. Methods: The patient had mild encephalopathy 14 days after influenza vaccination. Cerebrospinal fluid analysis revealed an increased cell count and a marked increase in myelin basic protein. Magnetic resonance imaging (MRI) demonstrated multiple lesions in the juxtacortical white matter. The patient was diagnosed with acute disseminated encephalomyelitis and treated with methylprednisolone pulse therapy. She recovered in 1 month. However, right retrobulbar optic neuritis appeared 2 months after discharge, and serum anti-aquaporin 4 antibodies were measured with a cell-based assay. Results: Anti-aquaporin 4 antibodies were present in the patient’s serum. She was treated with a prolonged course of oral prednisolone. The patient was negative for serum anti-aquaporin 4 antibodies 8 months after the second clinical event, and prednisolone was discontinued 13 months after the second clinical event. Serum anti-aquaporin 4 antibodies remained negative 4 months after the discontinuation of prednisolone. There was no evidence of relapse at 9 months after discontinuation of steroids. Conclusions: This case will expand the spectrum of anti-aquaporin-4 antibody-related central nervous system disorders. The measurement of anti-aquaporin 4 antibody may be considered in patients with a clinical diagnosis of acute disseminated encephalomyelitis and a second clinical event within a short interval. Ó 2014 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Keywords: Anti-aquaporin 4 antibody; Acute disseminated encephalomyelitis; Optic neuritis; Steroids; Vaccination
1. Introduction
⇑ Corresponding author at: Department of Pediatrics, Aichi Medical
University, 1-1 Yazako Karimata, Nagakute, Aichi 480-1195, Japan. Tel.: +81 561 62 3311; fax: +81 561 63 4835. E-mail address: [email protected] (A. Okumura).
Neuromyelitis optica (NMO), the coexistence of optic neuritis with myelitis, was recognized in the 19th century and had long been considered a variant of multiple sclerosis (MS) [1]. In 2004, Lennon et al. reported the presence of a circulating IgG autoantibody specific to
http://dx.doi.org/10.1016/j.braindev.2014.04.013 0387-7604/Ó 2014 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Please cite this article in press as: Okumura A et al. Anti-aquaporin 4 antibody-positive acute disseminated encephalomyelitis. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.04.013
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A. Okumura et al. / Brain & Development xxx (2014) xxx–xxx
NMO [2]. The astrocyte water channel protein aquaporin 4 (AQP4) was identified as the target of NMO autoantibodies [3]. At present, anti-AQP4 antibody-positive NMO is distinguished as a clinical entity independent from MS [4]. Thus, serological identification of antiAQP4 antibodies is currently included as an additional diagnostic criterion for NMO [5]. Optic neuritis and/or spinal cord lesions are frequent clinical manifestations of anti-AQP4-mediated central nervous system (CNS) disorders. However, the spectrum of anti-AQP4-mediated CNS disorders has not been sufficiently elucidated, especially in children. We encountered a young female patient with acute disseminated encephalomyelitis (ADEM) in whom anti-AQP4 antibodies were detected. Here, we report the clinical course and neuroimaging findings of this patient. 2. Patient report A previously healthy 4-years-old female was admitted to our hospital due to reduced consciousness and difficulty ambulating. She was the first child of nonconsanguineous healthy parents. Her past and family histories were unremarkable, and her psychomotor development was within normal limits. She received an influenza vaccine containing the A/California/7/2009 (H1N1) pdm09, A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 strains 14 days before the onset of neurological symptoms. Three days before admission, somnolence and behavioral changes such as irritability were observed in association with a low-grade fever of approximately 38 °C. Meningitis was suspected because she had nuchal rigidity. On admission, her body temperature was 37.0 °C, heart rate was 96 beats per minute, respiration rate was 24 per minute, and blood pressure was 98/58 mmHg. She was oriented but mildly somnolent. Physical examination was remarkable for nuchal rigidity, and neurological examination demonstrated hyperreflexia in both legs. Cerebrospinal fluid (CSF) analysis revealed an elevated cell count of 109 cells/ll, with normal protein and glucose levels. Laboratory data were otherwise unremarkable. A marked increase (>2000 pg/ ml) in myelin basic protein was found in the CSF on admission; no measurement of oligoclonal bands and glial fibrillary acidic protein was performed. Virological studies were negative for influenza virus (rapid antigen test), cytomegalovirus (enzyme-linked immunosorbent assay), herpes simplex virus (enzyme-linked immunosorbent assay), and Epstein–Barr virus (enzyme-linked immunosorbent assay). Electroencephalogram showed mild slowing of background activity. Cranial magnetic resonance imaging (MRI) demonstrated multiple high-intensity areas in the juxtacortical white matter on T2-weighted imaging and fluid-attenuated inversion recovery (Fig. 1). No lesions were found in the corpus
callosum, periventricular white matter, or deep gray matter, including the hypothalamus, cerebellum, brainstem, and cervical spinal cord. No abnormalities were recognized on funduscopic examination. The patient was diagnosed with ADEM and treated with methylprednisolone pulse therapy, intravenous acyclovir, and mannitol. Her somnolence resolved on the third day of admission, and neurological abnormalities resolved on the ninth day of admission. An enhance MRI on the tenth day of admission revealed a reduction in brain lesions and no contrast enhancement (Fig. 1). Oral prednisolone was prescribed at a dose of 1 mg/kg/ day for 1 week, followed by 0.5 mg/kg/day for 2 weeks. The patient was discharged from our hospital on day 13. An MRI at 1 month after the onset of the first clinical event showed that the cerebral lesions had disappeared (Fig. 1). Two months after discharge, the patient’s mother noticed disconjugate eye movements. Ophthalmological examination revealed retrobulbar optic neuritis of the right eye. MRI demonstrated swelling and increased intensity in the proximal portion of the right optic nerve on T2-weighed imaging (Fig. 1) but no brain or spinal lesions. The patient was again treated with methylprednisolone pulse therapy. The right optic nerve lesion resolved 9 days after the initiation of methylprednisolone pulse therapy (Fig. 1). Serum anti-AQP4 antibodies were detected in the patient’s serum during the second clinical event using cell-based assays [6]. Once anti-AQP4 antibodies were detected, the patient was prescribed a prolonged course of oral prednisolone with a gradual taper. After methylprednisolone pulse therapy, 2 mg/kg/day of prednisolone was given for 1 week. The dose of prednisolone was then reduced every 1–2 months. The patient tested negative for serum anti-AQP4 antibodies 8 months after the second clinical event. Prednisolone was discontinued 13 months after the second clinical event. The patient’s serum again tested negative for anti-AQP4 antibodies 4 months after the discontinuation of prednisolone. There was no evidence of relapse at 9 months after the discontinuation of steroids. The patient’s psychomotor development and growth were normal at the last follow-up at 79 months of age. 3. Discussion Our patient initially presented with the typical features of ADEM, which was followed by optic neuritis after the discontinuation of steroids. Serum anti-AQP4 antibodies were present during the acute period and disappeared after long-term treatment with oral steroids. This case will expand the spectrum of anti-AQP4 antibody-related CNS disorders. A revised consensus definition of ADEM was proposed by the International Pediatric Multiple Sclerosis
Please cite this article in press as: Okumura A et al. Anti-aquaporin 4 antibody-positive acute disseminated encephalomyelitis. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.04.013
A. Okumura et al. / Brain & Development xxx (2014) xxx–xxx
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Fig. 1. MRI findings. Top. Cerebral lesions during the first clinical event (fluid-attenuated inversion recovery). Left. Multiple high-intensity areas were seen in the juxtacortical cortical white matter. Middle. Cerebral lesions became less clear on the tenth day of admission. Right. No lesions were seen 1 month after onset. Bottom. Right optic nerve lesion during the second clinical event. Left. T2-weighted images at the onset of the second clinical event. Swelling and increased intensity (arrow) were observed in the proximal portion of the right optic nerve. Right. T2-weighted images 9 days later. Swelling and increased intensity were resolved (arrow).
Study Group in 2012 [7]. The clinical manifestation and neuroimaging features of our patients almost completely met this definition. The consensus definition makes mandatory the presence of encephalopathic symptoms, such as behavioral changes and an altered level of consciousness. Our patient had behavioral changes and a decreased level of consciousness at the onset of symptoms. MRI showed bilateral, asymmetrical, poorly demarcated areas of increased signal intensity in the juxtacortical white matter on T2-weighted imaging. No T1-hypointense lesions were present in the white matter. Although the size of the cerebral white matter lesions was relatively small, the neuroimaging features of our patient were largely compatible with the ADEM consensus definition. ADEM is a very rare initial manifestation of an antiAQP4 antibody-mediated brain disorder. McKeon et al. reported the clinical manifestation of anti-AQP4 antibodies in children [8]. The initial clinical presentation in 58 subjects included optic neuritis in 31 (53%), transverse myelitis in 13 (22%), optic neuritis and transverse myelitis in five (9%), and brain symptomatology in nine (16%). Although encephalopathy was seen in three of nine children presenting with brain symptomatology,
none of them was diagnosed with ADEM. HinoFukuyo et al. reported the clinical features of 18 children with anti-AQP4 antibodies in Japan [9]. Sixteen (94%) of 18 subjects had optic neuritis and/or transverse myelitis, and none had ADEM. Long et al. measured the seroprevalence of anti-AQP4 antibodies in 200 Chinese patients with several types of acute demyelinating disorders [10]. Two patients with ADEM were included, and both tested negative for anti-AQP4 antibodies. Saiki et al. reported the case of a 36-years-old woman with anti-AQP4 antibody-positive NMO associated with ADEM-like asymmetric tumefactive hyperintense lesions in the subcortical white matter after Mycoplasma pneumoniae infection [11]. These reports suggest that ADEM is an unusual manifestation of anti-AQP4 antibody-mediated brain disorders. In our patient, the interval between the first clinical encephalopathy event with multifocal cerebral lesions and the second event with right optic neuritis was 2 months. According to the consensus ADEM definition, these clinical events are operationally considered to represent a single acute event [7]. It is difficult to determine whether anti-AQP4 antibodies were present during the first encephalopathy event. If the two clinical
Please cite this article in press as: Okumura A et al. Anti-aquaporin 4 antibody-positive acute disseminated encephalomyelitis. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.04.013
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events represented a single acute event, anti-AQP4 antibodies would be related to both events. Another possibility is that anti-AQP4 antibodies were induced by the first event. If this is the case, the anti-AQP4 antibodies were only related to the second event with optic neuritis. Optic neuritis without additional brain lesions is a common manifestation of anti-AQP4 antibody-mediated brain disorders. In the series reported by McKeon et al., 31 of 58 children with anti-AQP4 antibodies had optic neuritis alone [8]. AQP4 is highly expressed on astrocyte end feet in the periependymal area including the optic nerves, spinal cord, peri-fourth ventricular and periaqueductal gray regions, hypothalamus, and brainstem. Thus, the optic nerve can be a target of anti-AQP4 antibody-mediated CNS disorders. In contrast, the role of anti-AQP4 antibodies in juxtacortical white matter lesions is insufficiently understood. The distribution of brain lesions cannot be explained by areas of high AQP4 expression. It is noteworthy that white matter lesions resembling ADEM or large tumefactive lesions have been infrequently reported in children with anti-AQP4 antibody-mediated CNS disorders, although pathogenesis of white matter lesions remains unknown [11,12]. It is important to note that patients with the anti-AQP4 antibody are at increased risk of progressive disability without appropriate treatment. The relationship between anti-AQP4 antibodies and white matter lesions is an important subject for future study. The relationship between influenza vaccination and the development of ADEM must be cautiously interpreted. Previous studies found that 5–12% of patients with ADEM had a history of vaccination within a month of presentation [13,14]. Several reports have noted ADEM after influenza vaccination, including reports from Japan [15,16]. However, no causal relationship between ADEM and influenza vaccination has been proven epidemiologically or pathologically. It is difficult to determine whether the influenza vaccine was the cause of ADEM in our patient. The treatment regimen of our patient was not easy to determine. Although there is no standard treatment regimen for ADEM, methylprednisolone pulse therapy followed by an oral steroid taper over 4–6 weeks is the most common treatment [17]. In contrast, long-term immunosuppressive treatment including azathioprine and rituximab is suggested once the diagnosis of NMO has been confirmed because NMO frequently shows a relapsing course, with incomplete recovery and worsening of neurological deficits [1]. Our patient responded well to steroids, although the second clinical event with neurological symptoms was seen after the discontinuation of steroids. Thus, slow tapering of oral steroids over 12 months was prescribed to treat the second event. The decision to discontinue steroids in our patient was made after the absence of anti-AQP4 antibodies was confirmed. Monitoring of anti-AQP4 antibodies may
be useful in determining whether treatment should be stopped. However, the possibility of recurrence remains. A long-term follow-up study found that the inter-attack interval ranged from 7 to 137 months [18]. In summary, we report the case of a young female with ADEM and typical clinical manifestations associated with anti-AQP4 antibody. Long-term steroid treatment was effective, with no residual neurological deficits and the disappearance of anti-AQP4 antibodies. Measurement of anti-AQP4 antibodies may be considered in patients with a clinical diagnosis of ADEM who have a second event after a short interval.
Acknowledgments We thank the patient and her families for their cooperation. This study is supported by the Grants from the Ministry of Health, Labor, and Welfare of Japan (H24Shinkou-Ippan-002 and H25-Nanji-Ippan-009), and the Grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (23591518). References [1] Trebst C, Jarius S, Berthele A, Paul F, Schippling S, Wildemann B, et al. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 2014;261:1–16. [2] Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004;364:2106–12. [3] Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005;202:473–7. [4] Jarius S, Wildemann B. AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 2010;6:383–92. [5] Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485–9. [6] Takahashi T, Fujihara K, Nakashima I, Misu T, Miyazawa I, Nakamura M, et al. Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 2007;130:1235–43. [7] Krupp LB, Tardieu M, Amato MP, Banwell B, Chitnis T, Dale RC, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler 2013;19:1261–7. [8] McKeon A, Lennon VA, Lotze T, Tenenbaum S, Ness JM, Rensel M, et al. CNS aquaporin-4 autoimmunity in children. Neurology 2008;71:93–100. [9] Hino-Fukuyo N, Takahashi T, Haginoya K, Uematsu M, Tsuchiya S, Fujihara K. Clinical features of Japanese pediatric patients with anti-aquaporin 4 antibody (In Japanese). No To Hattatsu 2011;43:359–65. [10] Long Y, Qiu W, Hu X, Peng F, Lu Z, Wang Y, et al. Antiaquaporin-4 antibody in Chinese patients with central nervous system inflammatory demyelinating disorders. Clin Neurol Neurosurg 2012;114:1131–4.
Please cite this article in press as: Okumura A et al. Anti-aquaporin 4 antibody-positive acute disseminated encephalomyelitis. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.04.013
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Please cite this article in press as: Okumura A et al. Anti-aquaporin 4 antibody-positive acute disseminated encephalomyelitis. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.04.013
