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SSPE following neonatal measles infection
SSPE Following Neonatal Measles Infection Yukio Sawaishi, MD*, Tamaki Abe, MD*†, Tamami Yano, MD*, Kohsei Ishikawa, MD†, and Goro Takada, MD* The authors report a case of subacute sclerosing panencephalitis in a child who had measles during the neonatal period. At 3 years, 6 months of age, over a period of a few weeks, the patient lost the ability to sit unaided as a result of progressive truncal ataxia, without apparent cognitive changes, simulating acute cerebellar ataxia. His symptoms improved in 1 month, and he was able to walk again with support, but mental alteration and periodic mild head nodding on awakening followed. His illness was diagnosed as subacute sclerosing panencephalitis on the basis of the elevated titers of measles antibodies in the cerebrospinal fluid. Measles infection before 1 year of age is a risk factor of subacute sclerosing panencephalitis, but reports about patients with neonatal measles infection are rare. Immaturity of the brain at the time of measles infection may not only be a risk factor but may also influence the clinical course of the disease. © 1999 by Elsevier Science Inc. All rights reserved. Sawaishi Y, Abe T, Yano T, Ishikawa K, Takada G. SSPE following neonatal measles infection. Pediatr Neurol 1999;20:63-65.
Introduction Subacute sclerosing panencephalitis (SSPE) is a slow viral infection of the central nervous system by the measles virus, primarily affecting children. Typically the neurologic dysfunction begins with behavioral difficulties that progress to myoclonic activity and eventually into complete neurologic deterioration. Measles (rubeola) virus
From the *Department of Pediatrics; Akita University School of Medicine; and †Department of Pediatrics; Yamamoto General Hospital; Akita, Japan.
© 1999 by Elsevier Science Inc. All rights reserved. PII S0887-8994(98)00101-5 ● 0887-8994/99/$20.00
infection below 1 year of age has been epidemiologically indicated to be one of the risk factors of SSPE [1]. However, SSPE patients with neonatal infection of measles virus have never been reported because of the rarity of neonates born of mothers free from measles virus infection or vaccination. The authors report a patient who was infected neonatally with the measles virus and exhibited an atypical clinical course of SSPE.
Case Report The male patient was born at term by normal delivery, with a birth weight of 2,998 gm and an Apgar score of 8 at 1 minute. On neonatal day 17, his mother was admitted to a local hospital for generalized morbilliform exanthema, cough, and high-grade fever. Three weeks later, her illness was diagnosed as measles (rubeola) because of the elevated complement fixation (CF) titer of serum measles antibody. On neonatal day 27 the patient also had mild exanthema, cough, and fever and was clinically diagnosed as having measles. His symptoms were so mild that they were treated in 1 week, without sequelae. At 1 year of age, his serum measles antibody titers were 1:8 (CF), 1:128 (hemagglutinin inhibition, [HI]), and 1:16 (neutralizing). He developed normally until the abrupt onset of unstable gait at the age of 3 years, 6 months. Within 1 week, he was unable to walk alone and was admitted to a local hospital on suspicion of acute cerebellar ataxia. Motor deficiencies progressed further during the next week, and he could hardly sit up without support. With conservative therapy, his symptoms gradually improved and within a month he was able to walk holding furniture, but mental deterioration and periodic mild head nodding during awakening were recognized. An electroencephalogram revealed periodic discharges (Fig 1) synchronized with the nodding movements, which appeared to be atonic seizures. His condition was diagnosed as SSPE on the basis of the abnormally elevated titers of the measles antibody in the cerebrospinal fluid; 1:32 (HI) and 1:32 (CF). Serum measles antibody titers were 1:512 (HI) and 1:1024 (CF). The cerebrospinal fluid contained 7/3 mononuclear cells/mL, protein 24 mg/dL, myelin basic protein 1.6 ng/mL, and oligoclonal IgG bands. Magnetic resonance imaging of the brain performed during the acute stage demonstrated diffuse highintensity lesions in the cerebral white matter on T2-weighted images (Fig 2). Approximately 3 months after onset, he was transferred to the authors’ hospital and treated with oral isoprinosine (100 mg/kg/day) and intraventricular human leukocyte interferon a (Sumiferon, Sumitomo, Osaka, Japan), which was started at 1 million U twice a week and then increased to 3 million U. His condition, however, developed relentlessly over the next 3 months into a bedridden and mute stage. Thereafter the progression of the disease appeared to stagnate for several months and then change to a gradual improvement. Electroencephalographic periodic complexes disappeared and the synchronized nodding movements became subtle. After about 1 year of the therapy, he was able to sit alone for minutes and to glance up in response to his name in spite of the progressive cerebral atrophy revealed by magnetic resonance imaging (Fig 3).
Communications should be addressed to: Dr. Sawaishi; Department of Pediatrics; Akita University School of Medicine; Hondo 1-1-1; Akita 010-8543, Japan. Received May 4, 1998; accepted July 9, 1998.
Sawaishi et al: SSPE After Neonatal Measles 63
Figure 1. Awake electroencephalogram 2 months after onset demonstrating periodic diffuse slow-wave complexes and slowing of the background activity.
Discussion Among accumulating reports of SSPE, data about patient neonatally infected with the measles virus are lacking, except for the recent report about an exceptional patient who developed a rapidly progressive type of SSPE at 4 months of age after intrauterine measles virus infection [2]. Fulminant types of SSPE, ending in death within several months, have occasionally been reported, but no preceding conditions were observed in common [3]. The authors’ patient seemed to be infected with the measles virus about 2 weeks after birth through contact with his mother. The rapidly progressive clinical course of this patient during the initial few weeks was similar to that of
Figure 2. Axial T2-weighted magnetic resonance image (TR 5 1,800 ms, TE 5 120 ms) 1 month after onset demonstrating diffuse periventricular symmetric hyperintense lesions.
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the fulminant type. However, after about 1 month of transient improvement, his clinical course was slowly progressive, expressing typical features of SSPE. The fluctuation of his initial clinical course over a few months is unusual. The authors speculate that neonatal infection with the measles virus is involved in the onset of SSPE. From an epidemiologic view, it is reported that measles infection under 1 year of age carries a risk of SSPE over 16 times greater than that of over 5 years of age [1]. Factors suggested as a cause include the immaturity of the infant, the fortuitous occurrence of another virus infection close to the measles infection, or the presence of measles
Figure 3. Axial T2-weighted magnetic resonance image (TR 5 3,800 ms, TE 5 108 ms) approximately 1 year after onset demonstrating diffuse cerebral atrophy and hyperintense lesions around the posterior horn of the lateral ventricle.
antibodies of maternal origin, which might promote genetic mutations resulting in a defective measles virus [4]. However, the latter two appear not to apply to this patient because of no other episode of neonatal infection and the probable lack of maternal measles antibodies during the pregnancy. It has also been hypothesized that the establishment of latency and subsequent development of SSPE may depend on the degree of infection and the extent of seeding in the brain [5]. Therefore, some age-dependent immaturity of the host at the time of measles infection may contribute to subsequent SSPE. In animal models the age-related susceptibility to neurotropic virus infection during the first few postnatal weeks have been documented with numerous viruses, including measles [6,7]. Moreover, it has been indicated that the age-related virulence of the neurotropic viruses is not determined by maturation of specific immune response or the blood brain barrier but depends on maturation of neuronal systems, which inhibit the virus to spread and change the pattern of infection from widespread to focal [8]. These experimental studies suggest that SSPE patients with neonatal measles infection may be classified as a special group with a somewhat different pathophysiologic background from those with later measles infection. More
clinical studies are needed to definitively characterize such a rare group.
References [1] Miller C, Farringtom CP, Harbert K. The epidemiology of subacute sclerosing panencephalitis in England and Wales 1970-1989. Int J Epidemiol 1992;21:998-1006. [2] Zwiauer K, Forstenpointner E, Popow-Kraupp T, Hauser E, Jellinger KA. Rapid progressive subacute sclerosing panencephalitis after perinatally acquired measles virus infection. Lancet 1995;345:1124. [3] Takayama S, Iwasaki Y, Yamanouchi H, Sugai K, Takashima S, Iwasaki A. Characteristic clinical features in a case of fulminant subacute sclerosing panencephalitis. Brain Dev 1994;16:132-5. [4] Kipps A, Dick G, Moodie JW. Measles and the central nervous system. Lancet 1983;2(8364):1406-10. [5] Aaby P, Bukh J, Lisse IM, Smits AJ. Risk factors in subacute sclerosing panencephalitis: Age- and sex-dependent host reactions or intensive exposure? Rev Infect Dis 1984;6:239-50. [6] Ogata A, Nagashima K, Hall WW, Ichikawa M, Kimura-Kuroda J, Yasui K. Japanese encephalitis virus neurotropism is dependent on the degree of neuronal maturity. J Virol 1991;65:880-6. [7] Swoveland PT, Johnson KP. Host age and cell type influence measles virus protein expression in the central nervous system. Virology 1989;170:131-8. [8] Oliver KR, Scallan MF, Dyson H, Fazakerley JF. Susceptibility to a neurotropic virus and its changing distribution in the developing brain is a function of CNS maturity. J Neurovirol 1997;3:38-48.
Sawaishi et al: SSPE After Neonatal Measles 65
Introduction Subacute sclerosing panencephalitis (SSPE) is a slow viral infection of the central nervous system by the measles virus, primarily affecting children. Typically the neurologic dysfunction begins with behavioral difficulties that progress to myoclonic activity and eventually into complete neurologic deterioration. Measles (rubeola) virus
From the *Department of Pediatrics; Akita University School of Medicine; and †Department of Pediatrics; Yamamoto General Hospital; Akita, Japan.
© 1999 by Elsevier Science Inc. All rights reserved. PII S0887-8994(98)00101-5 ● 0887-8994/99/$20.00
infection below 1 year of age has been epidemiologically indicated to be one of the risk factors of SSPE [1]. However, SSPE patients with neonatal infection of measles virus have never been reported because of the rarity of neonates born of mothers free from measles virus infection or vaccination. The authors report a patient who was infected neonatally with the measles virus and exhibited an atypical clinical course of SSPE.
Case Report The male patient was born at term by normal delivery, with a birth weight of 2,998 gm and an Apgar score of 8 at 1 minute. On neonatal day 17, his mother was admitted to a local hospital for generalized morbilliform exanthema, cough, and high-grade fever. Three weeks later, her illness was diagnosed as measles (rubeola) because of the elevated complement fixation (CF) titer of serum measles antibody. On neonatal day 27 the patient also had mild exanthema, cough, and fever and was clinically diagnosed as having measles. His symptoms were so mild that they were treated in 1 week, without sequelae. At 1 year of age, his serum measles antibody titers were 1:8 (CF), 1:128 (hemagglutinin inhibition, [HI]), and 1:16 (neutralizing). He developed normally until the abrupt onset of unstable gait at the age of 3 years, 6 months. Within 1 week, he was unable to walk alone and was admitted to a local hospital on suspicion of acute cerebellar ataxia. Motor deficiencies progressed further during the next week, and he could hardly sit up without support. With conservative therapy, his symptoms gradually improved and within a month he was able to walk holding furniture, but mental deterioration and periodic mild head nodding during awakening were recognized. An electroencephalogram revealed periodic discharges (Fig 1) synchronized with the nodding movements, which appeared to be atonic seizures. His condition was diagnosed as SSPE on the basis of the abnormally elevated titers of the measles antibody in the cerebrospinal fluid; 1:32 (HI) and 1:32 (CF). Serum measles antibody titers were 1:512 (HI) and 1:1024 (CF). The cerebrospinal fluid contained 7/3 mononuclear cells/mL, protein 24 mg/dL, myelin basic protein 1.6 ng/mL, and oligoclonal IgG bands. Magnetic resonance imaging of the brain performed during the acute stage demonstrated diffuse highintensity lesions in the cerebral white matter on T2-weighted images (Fig 2). Approximately 3 months after onset, he was transferred to the authors’ hospital and treated with oral isoprinosine (100 mg/kg/day) and intraventricular human leukocyte interferon a (Sumiferon, Sumitomo, Osaka, Japan), which was started at 1 million U twice a week and then increased to 3 million U. His condition, however, developed relentlessly over the next 3 months into a bedridden and mute stage. Thereafter the progression of the disease appeared to stagnate for several months and then change to a gradual improvement. Electroencephalographic periodic complexes disappeared and the synchronized nodding movements became subtle. After about 1 year of the therapy, he was able to sit alone for minutes and to glance up in response to his name in spite of the progressive cerebral atrophy revealed by magnetic resonance imaging (Fig 3).
Communications should be addressed to: Dr. Sawaishi; Department of Pediatrics; Akita University School of Medicine; Hondo 1-1-1; Akita 010-8543, Japan. Received May 4, 1998; accepted July 9, 1998.
Sawaishi et al: SSPE After Neonatal Measles 63
Figure 1. Awake electroencephalogram 2 months after onset demonstrating periodic diffuse slow-wave complexes and slowing of the background activity.
Discussion Among accumulating reports of SSPE, data about patient neonatally infected with the measles virus are lacking, except for the recent report about an exceptional patient who developed a rapidly progressive type of SSPE at 4 months of age after intrauterine measles virus infection [2]. Fulminant types of SSPE, ending in death within several months, have occasionally been reported, but no preceding conditions were observed in common [3]. The authors’ patient seemed to be infected with the measles virus about 2 weeks after birth through contact with his mother. The rapidly progressive clinical course of this patient during the initial few weeks was similar to that of
Figure 2. Axial T2-weighted magnetic resonance image (TR 5 1,800 ms, TE 5 120 ms) 1 month after onset demonstrating diffuse periventricular symmetric hyperintense lesions.
64
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the fulminant type. However, after about 1 month of transient improvement, his clinical course was slowly progressive, expressing typical features of SSPE. The fluctuation of his initial clinical course over a few months is unusual. The authors speculate that neonatal infection with the measles virus is involved in the onset of SSPE. From an epidemiologic view, it is reported that measles infection under 1 year of age carries a risk of SSPE over 16 times greater than that of over 5 years of age [1]. Factors suggested as a cause include the immaturity of the infant, the fortuitous occurrence of another virus infection close to the measles infection, or the presence of measles
Figure 3. Axial T2-weighted magnetic resonance image (TR 5 3,800 ms, TE 5 108 ms) approximately 1 year after onset demonstrating diffuse cerebral atrophy and hyperintense lesions around the posterior horn of the lateral ventricle.
antibodies of maternal origin, which might promote genetic mutations resulting in a defective measles virus [4]. However, the latter two appear not to apply to this patient because of no other episode of neonatal infection and the probable lack of maternal measles antibodies during the pregnancy. It has also been hypothesized that the establishment of latency and subsequent development of SSPE may depend on the degree of infection and the extent of seeding in the brain [5]. Therefore, some age-dependent immaturity of the host at the time of measles infection may contribute to subsequent SSPE. In animal models the age-related susceptibility to neurotropic virus infection during the first few postnatal weeks have been documented with numerous viruses, including measles [6,7]. Moreover, it has been indicated that the age-related virulence of the neurotropic viruses is not determined by maturation of specific immune response or the blood brain barrier but depends on maturation of neuronal systems, which inhibit the virus to spread and change the pattern of infection from widespread to focal [8]. These experimental studies suggest that SSPE patients with neonatal measles infection may be classified as a special group with a somewhat different pathophysiologic background from those with later measles infection. More
clinical studies are needed to definitively characterize such a rare group.
References [1] Miller C, Farringtom CP, Harbert K. The epidemiology of subacute sclerosing panencephalitis in England and Wales 1970-1989. Int J Epidemiol 1992;21:998-1006. [2] Zwiauer K, Forstenpointner E, Popow-Kraupp T, Hauser E, Jellinger KA. Rapid progressive subacute sclerosing panencephalitis after perinatally acquired measles virus infection. Lancet 1995;345:1124. [3] Takayama S, Iwasaki Y, Yamanouchi H, Sugai K, Takashima S, Iwasaki A. Characteristic clinical features in a case of fulminant subacute sclerosing panencephalitis. Brain Dev 1994;16:132-5. [4] Kipps A, Dick G, Moodie JW. Measles and the central nervous system. Lancet 1983;2(8364):1406-10. [5] Aaby P, Bukh J, Lisse IM, Smits AJ. Risk factors in subacute sclerosing panencephalitis: Age- and sex-dependent host reactions or intensive exposure? Rev Infect Dis 1984;6:239-50. [6] Ogata A, Nagashima K, Hall WW, Ichikawa M, Kimura-Kuroda J, Yasui K. Japanese encephalitis virus neurotropism is dependent on the degree of neuronal maturity. J Virol 1991;65:880-6. [7] Swoveland PT, Johnson KP. Host age and cell type influence measles virus protein expression in the central nervous system. Virology 1989;170:131-8. [8] Oliver KR, Scallan MF, Dyson H, Fazakerley JF. Susceptibility to a neurotropic virus and its changing distribution in the developing brain is a function of CNS maturity. J Neurovirol 1997;3:38-48.
Sawaishi et al: SSPE After Neonatal Measles 65