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Intravenous immunoglobulin therapy in acute disseminated encephalomyelitis
Intravenous Immunoglobulin Therapy in Acute Disseminated Encephalomyelitis Miki Nishikawa, MD,* Takashi Ichiyama, MD,* Takashi Hayashi, MD,* Kazunobu Ouchi, MD,† and Susumu Furukawa, MD* Three children ranging in age from 2 to 5 years with acute disseminated encephalomyelitis (ADEM) were successfully treated with high-dose intravenous immunoglobulin (IVIG). Their symptoms were somnolence, fever, headache, vomiting, and resting tremor. In all of these patients, it was difficult to distinguish the condition from viral encephalitis before analyzing the myelin basic protein. ADEM was diagnosed because of increased levels of myelin basic protein in their cerebrospinal fluid and abnormal high-signal intensity on T2-weighted magnetic resonance imaging. All patients were given IVIG at a dose of 400 mg/kg/day for 5 consecutive days. The patients rapidly regained consciousness in 14 hours, 2 days, and 4 days and demonstrated a complete clinical improvement within 18 days, 10 days, and 7 days of the initiation of the treatment, respectively. IVIG may prove useful as an alternative treatment to corticosteroids for ADEM. © 1999 by Elsevier Science Inc. All rights reserved. Nishikawa M, Ichiyama T, Hayashi T, Ouchi K, Furukawa S. Intravenous immunoglobulin therapy in acute disseminated encephalomyelitis. Pediatr Neurol 1999;21:583-586.
From the *Department of Pediatrics; Yamaguchi University School of Medicine; Ube; and †Department of Pediatrics; Saiseikai Shimonoseki General Hospital; Shimonoseki, Japan.
© 1999 by Elsevier Science Inc. All rights reserved. PII S0887-8994(99)00042-9 ● 0887-8994/99/$20.00
Introduction Acute disseminated encephalomyelitis (ADEM) is an acute or subacute demyelinating disorder of the central nervous system that typically occurs after a viral infection or immunization [1]. Laboratory findings suggest that the cerebrospinal fluid (CSF) may reveal an elevated level of myelin basic protein (MBP), increased pressure, and lymphocytosis, and magnetic resonance imaging (MRI) demonstrates increased signal intensity on T2-weighted images depicting multiple white matter lesions [1]. After the observation that intravenous immunoglobulin (IVIG) is effective for the treatment of idiopathic thrombocytopenia purpura [2], IVIG has been tried in several neuromuscular diseases related to immunologic disorders [3-5]. In Guillain-Barre´ syndrome, IVIG can take the place of plasma exchange because of the ease and rapidity of its administration, and it is safe even in unstable patients [6]. Although corticosteroid therapy is commonly used in ADEM, it is difficult to use corticosteroid therapy in the acute phase of ADEM without excluding acute encephalitis. The authors, up until this point, had encountered four pediatric patients with ADEM in their hospital over 10 years, without a standard therapeutic protocol. Thus they had no preconceived ideas regarding an established treatment for ADEM. Recently, IVIG therapy was successful in treating two patients with ADEM [7,8]. The authors also examined one of these patients with ADEM, Patient 1 and the proband in this study, who had a dramatic improvement after a clinical course of IVIG. Reported are three children with ADEM, including the proband, Patient 1, who exhibited rapid recovery after IVIG. Case Reports Patient 1. Patient 1 is a 5-year-old female who experienced vomiting and diarrhea for 2 days. After 1 week, she was admitted to the hospital because of a high-grade fever, right knee arthralgia, urinary incontinence, gait disturbance, and somnolence. On admission, her body temperature was 37.6°C. She demonstrated mild pyramidal and meningeal signs. The peripheral leukocyte count was 19,100/mm3, with 94.5% polymorphonuclear leukocytes, and the C-reactive protein (CRP) level was 4.96 mg/dL. The levels of serum electrolytes, blood urea nitrogen, creatinine, total protein, and ammonia were normal. A lumbar puncture gave clear fluid under normal pressure, with 94 leukocytes/mm3 (10% mononuclear cells), normal glucose (69 mg/dL), increased protein (47 mg/dL), and elevated IgG (6.7 mg/dL [normal levels are less than 1.5 mg/dL]). No bacteria were isolated on
Communications should be addressed to: Dr. Nishikawa; Department of Pediatrics; Yamaguchi University School of Medicine; 1144 Kogushi, Ube; Yamaguchi 755-8505, Japan. Received October 13, 1998; accepted March 23, 1999
Nishikawa et al: Intravenous Immunoglobulin/ADEM 583
Figure 1. (A) An axial T2-weighted MRI (TR ⫽ 3,000 ms, TE ⫽ 93 ms) demonstrating multiple areas of abnormal high-signal intensity in the cerebellum and white matter in both hemispheres (arrows). (B) An axial T2-weighted image (TR ⫽3,000 ms, TE ⫽ 93 ms) revealing small residual lesions in the cerebellum and white matter in both hemispheres.
culturing of CSF. The serum antibody titers for adenoviruses, influenza viruses, parainfluenza viruses, parvovirus B19, Mycoplasma pneumoniae, and Epstein-Barr virus were all negative. An electroencephalogram demonstrated diffuse delta-range slowing without seizure activity. Initially, she was diagnosed with viral encephalitis. MRI scanning of the brain was performed and demonstrated multiple high-intensity lesions in the cerebral subcortical white matter and cerebellum on T2-weighted images (Fig 1A). At that time, there was no information on MBP; the authors learned of the increased level of MBP 10 days later. She gradually became semicomatose within a few hours of admission. Eventually the authors diagnosed her with probable ADEM on the basis of the MRI findings and initiated IVIG therapy (400 mg/kg/day for 5 consecutive days).
On the second day of IVIG therapy, she gradually regained consciousness. On the fourth day of IVIG therapy, her nuchal rigidity had decreased. By the fifteenth day after the initiation of therapy, she was able to walk. On the eighteenth day, she had improved clinically, without any abnormal physical examination results. MRI performed on the twentieth day revealed that the lesions had resolved or were getting smaller (Fig 1B). On the twenty-first day, she was discharged from the hospital without any sequelae. Patient 2. A 5-year-old female experienced a febrile headache with nuchal rigidity from 20 days before admission to a nearby hospital. The peripheral leukocyte count was 18,500/mm3, and the CRP level was 2.9 mg/dL. The CSF contained 43 mg/dL glucose, 17 mg/dL protein, and 62 leukocytes/mm3. Because she was diagnosed as having viral or bacterial meningitis, she was treated with a parenteral antibiotic for treatment of bacterial meningitis over 4 weeks. Her meningeal symptoms, resting tremor of the upper limbs, and bilateral knee arthralgia, had not resolved. Brain MRI on the forty-fifth day demonstrated multiple abnormal high-intensity lesions in the basal ganglia and deep white matter around the lateral ventricle (Fig 2A). On the fiftieth day, she was transferred to the authors’ hospital because of suspicion of an intracranial neoplasm or fungal infection. She had a headache with nuchal rigidity, muscular hypertonicity, and increased deep tendon reflexes. The peripheral leukocyte count was 19,900/mm3, with 96% polymorphonuclear leukocytes, and the CRP level was 0.77 mg/dL. CSF studies revealed normal opening pressure, 72 leukocytes/mm3 (42% mononuclear cells), 48 mg/dL glucose, 47 mg/dL protein, 13.2 mg/dL MBP, and 3.9 mg/dL IgG. The elevated MBP results were reported on the seventh day after initiation of the IVIG therapy. The serum antibody titers for candida, aspergillus, toxoplasma, and Epstein-Barr virus were not increased. Microorganisms were not isolated from cultured CSF. The electroencephalogram demonstrated slow waves without epileptic discharge. On the second day in the hospital the authors diagnosed her with ADEM on the basis of the MRI findings and thus started IVIG therapy (400 mg/kg/day for 5 days). Within 4 days, her headache, fever, and nuchal rigidity were significantly improved. On the eighth day after the initiation of therapy the peripheral leukocyte count had decreased to 4,100/mm3. A second MRI on the eighth day revealed a partial resolution of the lesions (Fig 2B). On the tenth day, she had no neurologic deficits. On the fourteenth day, all blood examinations were normal, and she was discharged from the hospital without any sequelae. Patient 3. A 2-year-old male with a febrile headache, mild pyramidal signs, meningeal signs, and somnolence developed a painful enlargement of the parotid glands 5 days before admission to the hospital. He was diagnosed with aseptic meningitis associated with a mumps infection. The peripheral leukocyte count was 7,100/mm3, with 62.3% polymorphonuclear leukocytes, and the CRP level was 0.05 mg/dL. A lumbar
Figure 2. (A) An axial T2-weighted MRI (TR ⫽ 3,000 ms, TE ⫽ 93 ms) revealing abnormal high-signal lesions in the basal ganglia and white matter (arrows). (B) An axial T2-weighted image (TR ⫽ 3,000 ms, TE ⫽ 93 ms) demonstrating small residual lesions in the basal ganglia and white matter in both hemispheres.
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Figure 3. (A,B) Axial T2-weighted MRIs demonstrating multiple areas of abnormal high-signal intensity in the white matter in both hemispheres (arrows).
puncture produced clear fluid under 300 mm H2O pressure with 1,308 leukocytes/mm3 (40% mononuclear cells), normal glucose (65 mg/dL), elevated protein (55 mg/dL), and slightly increased IgG (2.1 mg/dL). On the second day after admission, his headache had worsened despite analgesics, and he developed somnolence. Brain MRI demonstrated multiple high-intensity lesions in the subcortical white matter of both hemispheres on T2-weighted images (Fig 3). The serum-specific IgM antibody titer for mumps on enzyme immunoassay was 4.99 on admission (positive level is greater than 1.21). No virus was isolated on culturing of CSF. He was diagnosed with probable ADEM associated with mumps infection on the basis of MRI findings. IVIG therapy (400 mg/kg/day for 5 consecutive days) was initiated. Within 14 hours, he gradually regained consciousness. By the fourth day after the initiation of therapy, he was able to walk. On the seventh day, all blood examinations were normal, and he was discharged from the hospital. The concentration of MBP before IVIG therapy increased to 6 ng/mL. The serum-specific IgM antibody titer for mumps on enzyme immunoassay was 7.61 on the fourteenth day after IVIG therapy. He was eventually diagnosed with definite ADEM associated with mumps infection on the basis of positive MBP, MRI lesions, and negative isolated mumps virus in CSF.
Discussion ADEM is an uncommon inflammatory demyelinating disease of the central nervous system. It is an acute illness that is typically associated with a viral infection or immunization. Patients with ADEM usually have a monophasic clinical course, lasting from 2 to 4 weeks. MRI demonstrates increased signal intensity lesions in the white matter on T2-weighted imaging. The MBP level, which is elevated in ADEM, is reported within 7-10 days at the authors’ hospital. Although the pathogenesis of ADEM remains unknown, it is hypothesized that the disorder results from an autoimmune reaction to myelin triggered by a virus [9]. Clinically, the diagnosis of ADEM is based on the typical MRI findings and the increased level of MBP. Because the MBP concentration cannot be determined quickly (at least in the authors’ hospital), it is difficult to make a definitive diagnosis of ADEM in the acute phase. Meanwhile, the treatment of ADEM with high-potency steroids, such as dexamethasone or methylprednisolone, has been initiated [1]. The
administration of corticosteroids is contraindicated for viral infections, especially viral encephalitis. Actually, it is worrisome to use corticosteroid therapy in the acute phase of ADEM without excluding the presence of acute encephalitis. Recent advances in the use of high-dose IVIG in a number of autoimmune disorders has led to its application to immune-mediated neurologic disorders, such as myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, and multiple sclerosis [4,10,11]. Postulated mechanisms of IVIG in neuromuscular diseases include the binding of immunoglobulin to Fc receptors on macrophages [12], anti-idiotypical antibodies in the infused immunoglobulin, feedback inhibition of antibody production, direct effects on antibody binding sites on nerves [13], nonspecific effects on natural killer cells, and increased activity of nonspecific T-suppressor cells [5]. Recently, there have been two reports that IVIG was effective in ADEM [7, 8]. Both patients (two males, 8 and 11 years of age, respectively) quickly recovered after IVIG therapy. Corticosteroid therapy has been commonly used in ADEM [13], although the definite mechanism is uncertain [14-16]. In addition, plasmapheresis has been used in patients with ADEM when steroids have failed [15]. There is no evidence based on controlled trials on the effect of corticosteroids. The reported patients were treated with IVIG because it was problematic to distinguish ADEM from viral encephalitis. These patients rapidly recovered consciousness in 14 hours, 2 days, or 4 days and responded within 18 days, 10 days, and 7 days of the initiation of the treatment with IVIG, respectively, despite the fact that an early recovery in ADEM generally is rare [8]. This report suggests that IVIG is a useful treatment for ADEM because of its rapid effectiveness. Regarding patients in which it is hard to distinguish ADEM from viral encephalitis clinically, the authors recommend IVIG treatment for suspected ADEM. Also, if IVIG has completely no effect on ADEM in the first stage, corticosteroid
Nishikawa et al: Intravenous Immunoglobulin/ADEM 585
therapy should be performed after confirming the increased level of MBP. References [1] Alvord EC Jr. Disseminated encephalomyelitis: Its variations in form and their relationships to other diseases of the nervous system. In: Vinken PJ, Bruyn GW, Klawans HL, eds. Handbook of clinical neurology, vol. 47, series 3. Amsterdam: Elsevier Science, 1985:467-502. [2] Imbach P, D’Apuzzo V, Hirt A, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenia purpura in childhood. Lancet 1981;1:1228-31. [3] Notarangelo LD, Duse M, Tiberti S, et al. Intravenous immunoglobulin in two children with Guillain-Barre´ syndrome. Eur J Pediatr 1993;152:372-4. [4] Soueidan SA, Dalakas MC. Treatment of autoimmune neuromuscular diseases with high-dose intravenous immune globulin. Pediatr Res 1993;33 (Suppl 1):95-100. [5] Cornblath DR, Chaudhry V, Griffin JW. Treatment of chronic inflammatory demyelinating polyneuropathy with intravenous immunoglobulin. Ann Neurol 1991;30:104-6. [6] Ropper AH. The Guillain-Barre´ syndrome. N Engl J Med 1992;326:1130-6. [7] Hahn JS, Siegler DJ, Enzmann D. Intravenous gammaglobulin therapy in recurrent acute disseminated encephalomyelitis. Neurology 1996;46:1173-5.
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[8] Klelman M, Brunquell P. Acute disseminated encephalomyelitis: Response to intravenous immunoglobulin? J Child Neurol 1995;10:481-3. [9] Baum PA, Barkovich AJ, Koch TK, Berg BO. Deep gray matter involvement in children with acute disseminated encephalomyelitis. Am J Neuroradiol 1994;15:1275-83. [10] Achiron A, Rotstein Z, Noy S, Mashiach S, Dulitzky M, Achiron R. Intravenous immunoglobulin treatment in the prevention of childbirth-associated acute exacerbations in multiple sclerosis: A pilot study. J Neurol 1996;243:25-8. [11] Nemni R, Amadio S, Fazio R, Galardi G, Previtali S, Comi G. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating neuropathy not responsive to other treatments. J Neurol Neurosurg Psychiatry 1994;57:43-5. [12] Dwyer JM. Manipulating the immune system with immune globulin. N Engl J Med 1992;326:107-16. [13] Zanetti M, Bigazzo PE. Anti-idiotypic immunity and autoimmunity. Eur J Immunol 1981;11:187-95. [14] Pasternak JF, De Vivo DC, Prensky AL. Steroid-responsive encephalomyelitis in childhood. Neurology 1980;30:481-6. [15] Kanter DS, Horensky D, Sperling RA, Kaplan JD, Malachowski ME, Churchill WH. Plasmapheresis in fulminant acute disseminated encephalomyelitis. Neurology 1995;45:824-7. [16] Stricker RB, Miller RG, Kiprov DD. Role of plasmapheresis in acute disseminated (postinfectious) encephalomyelitis. J Clin Apheresis 1992;7:173-9.
From the *Department of Pediatrics; Yamaguchi University School of Medicine; Ube; and †Department of Pediatrics; Saiseikai Shimonoseki General Hospital; Shimonoseki, Japan.
© 1999 by Elsevier Science Inc. All rights reserved. PII S0887-8994(99)00042-9 ● 0887-8994/99/$20.00
Introduction Acute disseminated encephalomyelitis (ADEM) is an acute or subacute demyelinating disorder of the central nervous system that typically occurs after a viral infection or immunization [1]. Laboratory findings suggest that the cerebrospinal fluid (CSF) may reveal an elevated level of myelin basic protein (MBP), increased pressure, and lymphocytosis, and magnetic resonance imaging (MRI) demonstrates increased signal intensity on T2-weighted images depicting multiple white matter lesions [1]. After the observation that intravenous immunoglobulin (IVIG) is effective for the treatment of idiopathic thrombocytopenia purpura [2], IVIG has been tried in several neuromuscular diseases related to immunologic disorders [3-5]. In Guillain-Barre´ syndrome, IVIG can take the place of plasma exchange because of the ease and rapidity of its administration, and it is safe even in unstable patients [6]. Although corticosteroid therapy is commonly used in ADEM, it is difficult to use corticosteroid therapy in the acute phase of ADEM without excluding acute encephalitis. The authors, up until this point, had encountered four pediatric patients with ADEM in their hospital over 10 years, without a standard therapeutic protocol. Thus they had no preconceived ideas regarding an established treatment for ADEM. Recently, IVIG therapy was successful in treating two patients with ADEM [7,8]. The authors also examined one of these patients with ADEM, Patient 1 and the proband in this study, who had a dramatic improvement after a clinical course of IVIG. Reported are three children with ADEM, including the proband, Patient 1, who exhibited rapid recovery after IVIG. Case Reports Patient 1. Patient 1 is a 5-year-old female who experienced vomiting and diarrhea for 2 days. After 1 week, she was admitted to the hospital because of a high-grade fever, right knee arthralgia, urinary incontinence, gait disturbance, and somnolence. On admission, her body temperature was 37.6°C. She demonstrated mild pyramidal and meningeal signs. The peripheral leukocyte count was 19,100/mm3, with 94.5% polymorphonuclear leukocytes, and the C-reactive protein (CRP) level was 4.96 mg/dL. The levels of serum electrolytes, blood urea nitrogen, creatinine, total protein, and ammonia were normal. A lumbar puncture gave clear fluid under normal pressure, with 94 leukocytes/mm3 (10% mononuclear cells), normal glucose (69 mg/dL), increased protein (47 mg/dL), and elevated IgG (6.7 mg/dL [normal levels are less than 1.5 mg/dL]). No bacteria were isolated on
Communications should be addressed to: Dr. Nishikawa; Department of Pediatrics; Yamaguchi University School of Medicine; 1144 Kogushi, Ube; Yamaguchi 755-8505, Japan. Received October 13, 1998; accepted March 23, 1999
Nishikawa et al: Intravenous Immunoglobulin/ADEM 583
Figure 1. (A) An axial T2-weighted MRI (TR ⫽ 3,000 ms, TE ⫽ 93 ms) demonstrating multiple areas of abnormal high-signal intensity in the cerebellum and white matter in both hemispheres (arrows). (B) An axial T2-weighted image (TR ⫽3,000 ms, TE ⫽ 93 ms) revealing small residual lesions in the cerebellum and white matter in both hemispheres.
culturing of CSF. The serum antibody titers for adenoviruses, influenza viruses, parainfluenza viruses, parvovirus B19, Mycoplasma pneumoniae, and Epstein-Barr virus were all negative. An electroencephalogram demonstrated diffuse delta-range slowing without seizure activity. Initially, she was diagnosed with viral encephalitis. MRI scanning of the brain was performed and demonstrated multiple high-intensity lesions in the cerebral subcortical white matter and cerebellum on T2-weighted images (Fig 1A). At that time, there was no information on MBP; the authors learned of the increased level of MBP 10 days later. She gradually became semicomatose within a few hours of admission. Eventually the authors diagnosed her with probable ADEM on the basis of the MRI findings and initiated IVIG therapy (400 mg/kg/day for 5 consecutive days).
On the second day of IVIG therapy, she gradually regained consciousness. On the fourth day of IVIG therapy, her nuchal rigidity had decreased. By the fifteenth day after the initiation of therapy, she was able to walk. On the eighteenth day, she had improved clinically, without any abnormal physical examination results. MRI performed on the twentieth day revealed that the lesions had resolved or were getting smaller (Fig 1B). On the twenty-first day, she was discharged from the hospital without any sequelae. Patient 2. A 5-year-old female experienced a febrile headache with nuchal rigidity from 20 days before admission to a nearby hospital. The peripheral leukocyte count was 18,500/mm3, and the CRP level was 2.9 mg/dL. The CSF contained 43 mg/dL glucose, 17 mg/dL protein, and 62 leukocytes/mm3. Because she was diagnosed as having viral or bacterial meningitis, she was treated with a parenteral antibiotic for treatment of bacterial meningitis over 4 weeks. Her meningeal symptoms, resting tremor of the upper limbs, and bilateral knee arthralgia, had not resolved. Brain MRI on the forty-fifth day demonstrated multiple abnormal high-intensity lesions in the basal ganglia and deep white matter around the lateral ventricle (Fig 2A). On the fiftieth day, she was transferred to the authors’ hospital because of suspicion of an intracranial neoplasm or fungal infection. She had a headache with nuchal rigidity, muscular hypertonicity, and increased deep tendon reflexes. The peripheral leukocyte count was 19,900/mm3, with 96% polymorphonuclear leukocytes, and the CRP level was 0.77 mg/dL. CSF studies revealed normal opening pressure, 72 leukocytes/mm3 (42% mononuclear cells), 48 mg/dL glucose, 47 mg/dL protein, 13.2 mg/dL MBP, and 3.9 mg/dL IgG. The elevated MBP results were reported on the seventh day after initiation of the IVIG therapy. The serum antibody titers for candida, aspergillus, toxoplasma, and Epstein-Barr virus were not increased. Microorganisms were not isolated from cultured CSF. The electroencephalogram demonstrated slow waves without epileptic discharge. On the second day in the hospital the authors diagnosed her with ADEM on the basis of the MRI findings and thus started IVIG therapy (400 mg/kg/day for 5 days). Within 4 days, her headache, fever, and nuchal rigidity were significantly improved. On the eighth day after the initiation of therapy the peripheral leukocyte count had decreased to 4,100/mm3. A second MRI on the eighth day revealed a partial resolution of the lesions (Fig 2B). On the tenth day, she had no neurologic deficits. On the fourteenth day, all blood examinations were normal, and she was discharged from the hospital without any sequelae. Patient 3. A 2-year-old male with a febrile headache, mild pyramidal signs, meningeal signs, and somnolence developed a painful enlargement of the parotid glands 5 days before admission to the hospital. He was diagnosed with aseptic meningitis associated with a mumps infection. The peripheral leukocyte count was 7,100/mm3, with 62.3% polymorphonuclear leukocytes, and the CRP level was 0.05 mg/dL. A lumbar
Figure 2. (A) An axial T2-weighted MRI (TR ⫽ 3,000 ms, TE ⫽ 93 ms) revealing abnormal high-signal lesions in the basal ganglia and white matter (arrows). (B) An axial T2-weighted image (TR ⫽ 3,000 ms, TE ⫽ 93 ms) demonstrating small residual lesions in the basal ganglia and white matter in both hemispheres.
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Figure 3. (A,B) Axial T2-weighted MRIs demonstrating multiple areas of abnormal high-signal intensity in the white matter in both hemispheres (arrows).
puncture produced clear fluid under 300 mm H2O pressure with 1,308 leukocytes/mm3 (40% mononuclear cells), normal glucose (65 mg/dL), elevated protein (55 mg/dL), and slightly increased IgG (2.1 mg/dL). On the second day after admission, his headache had worsened despite analgesics, and he developed somnolence. Brain MRI demonstrated multiple high-intensity lesions in the subcortical white matter of both hemispheres on T2-weighted images (Fig 3). The serum-specific IgM antibody titer for mumps on enzyme immunoassay was 4.99 on admission (positive level is greater than 1.21). No virus was isolated on culturing of CSF. He was diagnosed with probable ADEM associated with mumps infection on the basis of MRI findings. IVIG therapy (400 mg/kg/day for 5 consecutive days) was initiated. Within 14 hours, he gradually regained consciousness. By the fourth day after the initiation of therapy, he was able to walk. On the seventh day, all blood examinations were normal, and he was discharged from the hospital. The concentration of MBP before IVIG therapy increased to 6 ng/mL. The serum-specific IgM antibody titer for mumps on enzyme immunoassay was 7.61 on the fourteenth day after IVIG therapy. He was eventually diagnosed with definite ADEM associated with mumps infection on the basis of positive MBP, MRI lesions, and negative isolated mumps virus in CSF.
Discussion ADEM is an uncommon inflammatory demyelinating disease of the central nervous system. It is an acute illness that is typically associated with a viral infection or immunization. Patients with ADEM usually have a monophasic clinical course, lasting from 2 to 4 weeks. MRI demonstrates increased signal intensity lesions in the white matter on T2-weighted imaging. The MBP level, which is elevated in ADEM, is reported within 7-10 days at the authors’ hospital. Although the pathogenesis of ADEM remains unknown, it is hypothesized that the disorder results from an autoimmune reaction to myelin triggered by a virus [9]. Clinically, the diagnosis of ADEM is based on the typical MRI findings and the increased level of MBP. Because the MBP concentration cannot be determined quickly (at least in the authors’ hospital), it is difficult to make a definitive diagnosis of ADEM in the acute phase. Meanwhile, the treatment of ADEM with high-potency steroids, such as dexamethasone or methylprednisolone, has been initiated [1]. The
administration of corticosteroids is contraindicated for viral infections, especially viral encephalitis. Actually, it is worrisome to use corticosteroid therapy in the acute phase of ADEM without excluding the presence of acute encephalitis. Recent advances in the use of high-dose IVIG in a number of autoimmune disorders has led to its application to immune-mediated neurologic disorders, such as myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, and multiple sclerosis [4,10,11]. Postulated mechanisms of IVIG in neuromuscular diseases include the binding of immunoglobulin to Fc receptors on macrophages [12], anti-idiotypical antibodies in the infused immunoglobulin, feedback inhibition of antibody production, direct effects on antibody binding sites on nerves [13], nonspecific effects on natural killer cells, and increased activity of nonspecific T-suppressor cells [5]. Recently, there have been two reports that IVIG was effective in ADEM [7, 8]. Both patients (two males, 8 and 11 years of age, respectively) quickly recovered after IVIG therapy. Corticosteroid therapy has been commonly used in ADEM [13], although the definite mechanism is uncertain [14-16]. In addition, plasmapheresis has been used in patients with ADEM when steroids have failed [15]. There is no evidence based on controlled trials on the effect of corticosteroids. The reported patients were treated with IVIG because it was problematic to distinguish ADEM from viral encephalitis. These patients rapidly recovered consciousness in 14 hours, 2 days, or 4 days and responded within 18 days, 10 days, and 7 days of the initiation of the treatment with IVIG, respectively, despite the fact that an early recovery in ADEM generally is rare [8]. This report suggests that IVIG is a useful treatment for ADEM because of its rapid effectiveness. Regarding patients in which it is hard to distinguish ADEM from viral encephalitis clinically, the authors recommend IVIG treatment for suspected ADEM. Also, if IVIG has completely no effect on ADEM in the first stage, corticosteroid
Nishikawa et al: Intravenous Immunoglobulin/ADEM 585
therapy should be performed after confirming the increased level of MBP. References [1] Alvord EC Jr. Disseminated encephalomyelitis: Its variations in form and their relationships to other diseases of the nervous system. In: Vinken PJ, Bruyn GW, Klawans HL, eds. Handbook of clinical neurology, vol. 47, series 3. Amsterdam: Elsevier Science, 1985:467-502. [2] Imbach P, D’Apuzzo V, Hirt A, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenia purpura in childhood. Lancet 1981;1:1228-31. [3] Notarangelo LD, Duse M, Tiberti S, et al. Intravenous immunoglobulin in two children with Guillain-Barre´ syndrome. Eur J Pediatr 1993;152:372-4. [4] Soueidan SA, Dalakas MC. Treatment of autoimmune neuromuscular diseases with high-dose intravenous immune globulin. Pediatr Res 1993;33 (Suppl 1):95-100. [5] Cornblath DR, Chaudhry V, Griffin JW. Treatment of chronic inflammatory demyelinating polyneuropathy with intravenous immunoglobulin. Ann Neurol 1991;30:104-6. [6] Ropper AH. The Guillain-Barre´ syndrome. N Engl J Med 1992;326:1130-6. [7] Hahn JS, Siegler DJ, Enzmann D. Intravenous gammaglobulin therapy in recurrent acute disseminated encephalomyelitis. Neurology 1996;46:1173-5.
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[8] Klelman M, Brunquell P. Acute disseminated encephalomyelitis: Response to intravenous immunoglobulin? J Child Neurol 1995;10:481-3. [9] Baum PA, Barkovich AJ, Koch TK, Berg BO. Deep gray matter involvement in children with acute disseminated encephalomyelitis. Am J Neuroradiol 1994;15:1275-83. [10] Achiron A, Rotstein Z, Noy S, Mashiach S, Dulitzky M, Achiron R. Intravenous immunoglobulin treatment in the prevention of childbirth-associated acute exacerbations in multiple sclerosis: A pilot study. J Neurol 1996;243:25-8. [11] Nemni R, Amadio S, Fazio R, Galardi G, Previtali S, Comi G. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating neuropathy not responsive to other treatments. J Neurol Neurosurg Psychiatry 1994;57:43-5. [12] Dwyer JM. Manipulating the immune system with immune globulin. N Engl J Med 1992;326:107-16. [13] Zanetti M, Bigazzo PE. Anti-idiotypic immunity and autoimmunity. Eur J Immunol 1981;11:187-95. [14] Pasternak JF, De Vivo DC, Prensky AL. Steroid-responsive encephalomyelitis in childhood. Neurology 1980;30:481-6. [15] Kanter DS, Horensky D, Sperling RA, Kaplan JD, Malachowski ME, Churchill WH. Plasmapheresis in fulminant acute disseminated encephalomyelitis. Neurology 1995;45:824-7. [16] Stricker RB, Miller RG, Kiprov DD. Role of plasmapheresis in acute disseminated (postinfectious) encephalomyelitis. J Clin Apheresis 1992;7:173-9.