533845
research-article2015
MSJ0010.1177/1352458514533845Multiple Sclerosis JournalK Shinoda, H Asahara
MULTIPLE SCLEROSIS MSJ JOURNAL
Case Report
Multiphasic acute disseminated encephalomyelitis associated with atypical rubella virus infection
Multiple Sclerosis Journal 2015, Vol. 21(2) 252–254 DOI: 10.1177/ 1352458514533845 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Koji Shinoda, Hideaki Asahara, Taira Uehara, Katsue Miyoshi, Satoshi O Suzuki, Toru Iwaki and Jun-ichi Kira
Abstract: We report the first case of an occurrence of multiphasic acute disseminated encephalomyelitis (ADEM) associated with atypical rubella virus infection with no rash and long-term increased titers of serum anti-rubella IgM in a 17-year-old male who had no history of rubella vaccination. He suffered from at least six clinical exacerbations with disseminated hyperintense lesions on FLAIR MR images during the course of 18 months. Repeated methylprednisolone pulse therapy and intravenous immunoglobulin therapy resolved the exacerbations. In patients with multiphasic ADEM of unknown etiology, clinicians should also consider the possibility of preceding infection with rubella virus. Keywords: Multiphasic acute disseminated encephalomyelitis, rubella, MRI, brain biopsy Date received: 6 January 2014; revised: 11 March 2014; accepted: 9 April 2014
Introduction Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder, and typically follows a monophasic course.1 Nevertheless, non-monophasic forms have been reported in 5.5– 21% of cases,1 and are classified into recurrent and multiphasic ADEM.2 In this report, we describe the first patient with multiphasic ADEM associated with atypical rubella virus infection. Case report The patient was a 17-year-old male who was admitted to our hospital because of disorientation, dysarthria, and left hemiparesis that developed one week after fever onset without a rash. He had no history of rubella vaccination. His cerebrospinal fluid (CSF) was hypercellular (41/µl, all mononuclear cells) with normal total protein and absence of oligoclonal immunoglobulin G (IgG) bands. Anti-nuclear antibodies were positive, whereas other autoantibodies were negative, including anti-SS-A, anti-SS-B, antids-DNA, anti-thyroglobulin, anti-thyroid peroxidase, anti-neutrophil cytoplasmic, and anti-aquaporin-4 antibodies. There was no evidence of acute infection of herpes simplex virus (HSV), varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, influenza virus,
measles virus, and mycoplasma in the serum. HSVDNA was not detected by polymerase chain reaction (PCR) in his CSF. Head magnetic resonance imaging (MRI) revealed disseminated hyperintense lesions at the bilateral cerebellar peduncles, left basal ganglia, and corpus callosum on fluid-attenuated inversion recovery (FLAIR) images with partial gadolinium enhancement (Figure 1(a)). Intravenous methylprednisolone pulse therapy (1000 mg/day for three days) followed by oral prednisolone (50 mg/day with gradual tapering) resolved all the symptoms except for mild memory disturbance within a few weeks. Two months later, somnolence and left hemiparesis recurred. CSF showed mild hypercellularity (10/µl) and increased myelin basic protein (931 pg/ml). MRI revealed new hyperintense lesions in the right periventricular white matter (Figure 1(b)). After additional methylprednisolone pulse therapy, the somnolence disappeared immediately and the hemiparesis recovered completely in a few weeks. Although he had a good response to corticosteroids, he experienced at least four exacerbations within one year, during which we confirmed mild alterations in consciousness, cerebellar ataxia, and new lesions on MRI (Figure 1(c)). At six months after the onset, a brain biopsy was performed for the left anterior lobe lesion to rule out the possibility of a primary central nervous system
Correspondence to: Jun-ichi Kira Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. [email protected]. ac.jp Koji Shinoda Taira Uehara Jun-ichi Kira Satoshi O Suzuki Toru Iwaki Kyushu University, Japan Hideaki Asahara Japanese Red Cross Hiroshima College of Nursing, Japan Katsue Miyoshi Kushiro Kita Hospital, Japan
252 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV OF CONNECTICUT on June 21, 2015
K Shinoda, H Asahara et al.
Figure 1. Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance images (MRI): (a) on the first admission day; (b) two months later with new lesions (arrows); (c) five months later with a new lesion (arrow). Brain pathology images: (d) perivenous infiltration of mononuclear cells in the white matter (×10, hematoxylin-eosin staining); (e) perivenous infiltration of chronic inflammatory cells including macrophages with hemosiderin deposition (×40, hematoxylin-eosin staining); (f) perivenous myelin pallor in the white matter (×20, Klüver-Barrera staining); (g) perivenous infiltration of lymphocytes and macrophages/activated microglia (×20, immunostaining for CD45); (h) macrophages and microglia (×20, immunostaining for CD68). http://msj.sagepub.com 253
Downloaded from msj.sagepub.com at UNIV OF CONNECTICUT on June 21, 2015
Multiple Sclerosis Journal 21(2) lymphoma. The pathological examination revealed no malignancy and mild to moderate infiltration of lymphocytes and macrophages mainly around the venules of the white matter and the subarachnoid space (Figure 1(d) and (e)). Myelin was largely preserved. However, myelin pallor was focally observed around the venules with perivascular inflammatory infiltrates (Figure 1(f)–(h)), compatible with ADEM. At the beginning, we did not examine anti-rubella IgG and IgM because we considered that the priority was relatively low according to his clinical presentation without a rash and the relative rareness of rubella at that time in Japan. At 10 months after the disease onset, we unexpectedly found increased titers of serum antirubella IgM, and the elevation was confirmed at the time of his first relapse as far as we could examine retrospectively. Subsequently, we treated the patient with intravenous immunoglobulin therapy (0.4 g/kg daily for five days) and methylprednisolone pulse therapy at the time of clinical exacerbations. The serum anti-rubella IgM titers diminished gradually and became undetectable at 18 months after the disease onset. Since that time, he has not suffered from any clinical exacerbations or changes on head MRI without medication for four years.
lines of evidence indicate a potential role of rubella virus in the pathogenesis of demyelinating diseases including multiphasic ADEM.
Discussion Rubella is a febrile rash illness caused by rubella virus and characterized by an erythematous, maculopapular rash, mild fever, and lymphadenopathy, but may have an atypical course.3 Although the World Health Organization (WHO) Region of America and European Region have established rubella elimination goals of 2010 and 2015, respectively, rubella is still a common disease in developing countries and outbreaks of rubella (>2000 cases) were reported in Japan, Romania, and Poland in 2012.4 During the course of rubella infection, postinfectious encephalitis has been documented with an incidence of one per 5000–10,000 cases,3 and can also be followed by rubella without a rash.5 However, there are no reports of recurrent or multiphasic ADEM in patients with rubella. Regarding the molecular mechanism, it has been reported that an antibody response to the surface glycoprotein E2 of rubella virus was elevated in multiple sclerosis (MS) patients compared with a normal population6 and that sequence homology was found between E2 and myelin oligodendrocyte glycoprotein.7 These
1.
Tenembaum S, Chitnis T, Ness J, et al. Acute disseminated encephalomyelitis. Neurology 2007; 68: S23–S36.
2.
Krupp LB, Banwell B and Tenembaum S. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology 2007; 68: S7–S12.
3.
Banatvala JE and Brown DWG. Rubella. Lancet 2004; 363: 1127–1137.
4.
Centers for Disease Control and Prevention (CDC). Rubella and congenital rubella syndrome control and elimination – global progress, 2010–2012. MMWR Morb Wkly Rep 2013; 62: 983–986.
5.
Guler E, Davutoglu M, Guler S, et al. Encephalitis in a child during atypical course of rubella. Infection 2009; 37: 65–66.
6.
Nath A and Wolinsky JS. Antibody response to rubella virus structural proteins in multiple sclerosis. Ann Neurol 1990; 27: 533–536.
7.
Besson Duvanel C, Honegger P and Matthieu JM. Antibodies directed against rubella virus induce demyelination in aggregating rat brain cell cultures. J Neurosci Res 2001; 65: 446–454.
In our case, a patient with no history of rubella or its vaccination presented with multiphasic ADEM, and the diagnosis was supported by the pathological examination. The laboratory data revealed long-term elevated titers of serum anti-rubella IgM, which suggested the involvement of rubella virus infection in the pathogenesis. Clinicians should also consider an association with rubella virus infection in patients with multiphasic ADEM of unknown etiology, even if they lack the typical rash, especially in countries in which rubella has not been eliminated. Conflict of interest None declared. Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
References
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
254 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV OF CONNECTICUT on June 21, 2015
research-article2015
MSJ0010.1177/1352458514533845Multiple Sclerosis JournalK Shinoda, H Asahara
MULTIPLE SCLEROSIS MSJ JOURNAL
Case Report
Multiphasic acute disseminated encephalomyelitis associated with atypical rubella virus infection
Multiple Sclerosis Journal 2015, Vol. 21(2) 252–254 DOI: 10.1177/ 1352458514533845 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Koji Shinoda, Hideaki Asahara, Taira Uehara, Katsue Miyoshi, Satoshi O Suzuki, Toru Iwaki and Jun-ichi Kira
Abstract: We report the first case of an occurrence of multiphasic acute disseminated encephalomyelitis (ADEM) associated with atypical rubella virus infection with no rash and long-term increased titers of serum anti-rubella IgM in a 17-year-old male who had no history of rubella vaccination. He suffered from at least six clinical exacerbations with disseminated hyperintense lesions on FLAIR MR images during the course of 18 months. Repeated methylprednisolone pulse therapy and intravenous immunoglobulin therapy resolved the exacerbations. In patients with multiphasic ADEM of unknown etiology, clinicians should also consider the possibility of preceding infection with rubella virus. Keywords: Multiphasic acute disseminated encephalomyelitis, rubella, MRI, brain biopsy Date received: 6 January 2014; revised: 11 March 2014; accepted: 9 April 2014
Introduction Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder, and typically follows a monophasic course.1 Nevertheless, non-monophasic forms have been reported in 5.5– 21% of cases,1 and are classified into recurrent and multiphasic ADEM.2 In this report, we describe the first patient with multiphasic ADEM associated with atypical rubella virus infection. Case report The patient was a 17-year-old male who was admitted to our hospital because of disorientation, dysarthria, and left hemiparesis that developed one week after fever onset without a rash. He had no history of rubella vaccination. His cerebrospinal fluid (CSF) was hypercellular (41/µl, all mononuclear cells) with normal total protein and absence of oligoclonal immunoglobulin G (IgG) bands. Anti-nuclear antibodies were positive, whereas other autoantibodies were negative, including anti-SS-A, anti-SS-B, antids-DNA, anti-thyroglobulin, anti-thyroid peroxidase, anti-neutrophil cytoplasmic, and anti-aquaporin-4 antibodies. There was no evidence of acute infection of herpes simplex virus (HSV), varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, influenza virus,
measles virus, and mycoplasma in the serum. HSVDNA was not detected by polymerase chain reaction (PCR) in his CSF. Head magnetic resonance imaging (MRI) revealed disseminated hyperintense lesions at the bilateral cerebellar peduncles, left basal ganglia, and corpus callosum on fluid-attenuated inversion recovery (FLAIR) images with partial gadolinium enhancement (Figure 1(a)). Intravenous methylprednisolone pulse therapy (1000 mg/day for three days) followed by oral prednisolone (50 mg/day with gradual tapering) resolved all the symptoms except for mild memory disturbance within a few weeks. Two months later, somnolence and left hemiparesis recurred. CSF showed mild hypercellularity (10/µl) and increased myelin basic protein (931 pg/ml). MRI revealed new hyperintense lesions in the right periventricular white matter (Figure 1(b)). After additional methylprednisolone pulse therapy, the somnolence disappeared immediately and the hemiparesis recovered completely in a few weeks. Although he had a good response to corticosteroids, he experienced at least four exacerbations within one year, during which we confirmed mild alterations in consciousness, cerebellar ataxia, and new lesions on MRI (Figure 1(c)). At six months after the onset, a brain biopsy was performed for the left anterior lobe lesion to rule out the possibility of a primary central nervous system
Correspondence to: Jun-ichi Kira Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. [email protected]. ac.jp Koji Shinoda Taira Uehara Jun-ichi Kira Satoshi O Suzuki Toru Iwaki Kyushu University, Japan Hideaki Asahara Japanese Red Cross Hiroshima College of Nursing, Japan Katsue Miyoshi Kushiro Kita Hospital, Japan
252 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV OF CONNECTICUT on June 21, 2015
K Shinoda, H Asahara et al.
Figure 1. Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance images (MRI): (a) on the first admission day; (b) two months later with new lesions (arrows); (c) five months later with a new lesion (arrow). Brain pathology images: (d) perivenous infiltration of mononuclear cells in the white matter (×10, hematoxylin-eosin staining); (e) perivenous infiltration of chronic inflammatory cells including macrophages with hemosiderin deposition (×40, hematoxylin-eosin staining); (f) perivenous myelin pallor in the white matter (×20, Klüver-Barrera staining); (g) perivenous infiltration of lymphocytes and macrophages/activated microglia (×20, immunostaining for CD45); (h) macrophages and microglia (×20, immunostaining for CD68). http://msj.sagepub.com 253
Downloaded from msj.sagepub.com at UNIV OF CONNECTICUT on June 21, 2015
Multiple Sclerosis Journal 21(2) lymphoma. The pathological examination revealed no malignancy and mild to moderate infiltration of lymphocytes and macrophages mainly around the venules of the white matter and the subarachnoid space (Figure 1(d) and (e)). Myelin was largely preserved. However, myelin pallor was focally observed around the venules with perivascular inflammatory infiltrates (Figure 1(f)–(h)), compatible with ADEM. At the beginning, we did not examine anti-rubella IgG and IgM because we considered that the priority was relatively low according to his clinical presentation without a rash and the relative rareness of rubella at that time in Japan. At 10 months after the disease onset, we unexpectedly found increased titers of serum antirubella IgM, and the elevation was confirmed at the time of his first relapse as far as we could examine retrospectively. Subsequently, we treated the patient with intravenous immunoglobulin therapy (0.4 g/kg daily for five days) and methylprednisolone pulse therapy at the time of clinical exacerbations. The serum anti-rubella IgM titers diminished gradually and became undetectable at 18 months after the disease onset. Since that time, he has not suffered from any clinical exacerbations or changes on head MRI without medication for four years.
lines of evidence indicate a potential role of rubella virus in the pathogenesis of demyelinating diseases including multiphasic ADEM.
Discussion Rubella is a febrile rash illness caused by rubella virus and characterized by an erythematous, maculopapular rash, mild fever, and lymphadenopathy, but may have an atypical course.3 Although the World Health Organization (WHO) Region of America and European Region have established rubella elimination goals of 2010 and 2015, respectively, rubella is still a common disease in developing countries and outbreaks of rubella (>2000 cases) were reported in Japan, Romania, and Poland in 2012.4 During the course of rubella infection, postinfectious encephalitis has been documented with an incidence of one per 5000–10,000 cases,3 and can also be followed by rubella without a rash.5 However, there are no reports of recurrent or multiphasic ADEM in patients with rubella. Regarding the molecular mechanism, it has been reported that an antibody response to the surface glycoprotein E2 of rubella virus was elevated in multiple sclerosis (MS) patients compared with a normal population6 and that sequence homology was found between E2 and myelin oligodendrocyte glycoprotein.7 These
1.
Tenembaum S, Chitnis T, Ness J, et al. Acute disseminated encephalomyelitis. Neurology 2007; 68: S23–S36.
2.
Krupp LB, Banwell B and Tenembaum S. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology 2007; 68: S7–S12.
3.
Banatvala JE and Brown DWG. Rubella. Lancet 2004; 363: 1127–1137.
4.
Centers for Disease Control and Prevention (CDC). Rubella and congenital rubella syndrome control and elimination – global progress, 2010–2012. MMWR Morb Wkly Rep 2013; 62: 983–986.
5.
Guler E, Davutoglu M, Guler S, et al. Encephalitis in a child during atypical course of rubella. Infection 2009; 37: 65–66.
6.
Nath A and Wolinsky JS. Antibody response to rubella virus structural proteins in multiple sclerosis. Ann Neurol 1990; 27: 533–536.
7.
Besson Duvanel C, Honegger P and Matthieu JM. Antibodies directed against rubella virus induce demyelination in aggregating rat brain cell cultures. J Neurosci Res 2001; 65: 446–454.
In our case, a patient with no history of rubella or its vaccination presented with multiphasic ADEM, and the diagnosis was supported by the pathological examination. The laboratory data revealed long-term elevated titers of serum anti-rubella IgM, which suggested the involvement of rubella virus infection in the pathogenesis. Clinicians should also consider an association with rubella virus infection in patients with multiphasic ADEM of unknown etiology, even if they lack the typical rash, especially in countries in which rubella has not been eliminated. Conflict of interest None declared. Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
References
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
254 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV OF CONNECTICUT on June 21, 2015
