Wild-type measles virus in brain tissue of children with subacute sclerosing panencephalitis, Argentina.We studied eight children who had measles at 6 to 10 months of age during the 1998 Argentine measles outbreak and in whom subacute sclerosing panencephalitis Subacute Sclerosing Panencephalitis Definition
Subacute sclerosing panencephalitis is a rare, progressive brain disorder caused by an abnormal immune response to the measles virus. developed 4 years later. We report the genetic characterization of brain tissue-associated measles virus measles virus
An RNA virus of the genus Morbillivirus that causes measles in humans. Also called rubeola virus. samples from three patients. Phylogenetic phy·lo·ge·net·ic
1. Of or relating to phylogeny or phylogenetics.
2. Relating to or based on evolutionary development or history. relationships clustered these viruses with the wild-type D6 genotype isolated during the 1998 outbreak. The children received measles vaccine; however, vaccinal vaccinal /vac·ci·nal/ (vak´si-n'l)
1. pertaining to vaccine or to vaccination.
2. having protective qualities when used by way of inoculation.
1. strains were not found.
Measles is often incorrectly regarded as a mild disease, and priority is not given to measles elimination programs in some countries (1). Nevertheless, substantial progress has been made in eliminating measles virus from the Americas through massive vaccination campaigns and maintaining high measles population immunity over time. From 1990 to 1996, measles cases declined from 250,000 to 2,109; however, in 1997, measles reemerged in the Americas, with 70,983 confirmed cases. From the last Argentine outbreak (July 1997-May 1999), 10,354 confirmed measles cases were reported, most of them in unvaccinated preschool-aged children in the greater Buenos Aires Greater Buenos Aires (Spanish: Gran Buenos Aires) is the metropolitan area of the city of Buenos Aires, Argentina, which consists of the Federal Capital and the following 24 partidos (administrative subdivisions) of the Province of Buenos Aires:
Although measles virus (Morbillivirus Morbillivirus /Mor·bil·li·vi·rus/ (-vi?rus) measles-like viruses; a genus of viruses of the family Paramyxoviridae, including the agents of measles and canine distemper.
n. genus, Paramyxovirus Paramyxovirus
A subgroup of myxoviruses that includes the viruses of mumps, measles, parainfluenza, respiratory syncytial (RS) disease, and Newcastle disease. family) is not highly neurotropic neurotropic
pertaining to or emanating from neurotrophy, e.g. neurotropic osteopathy. , it can establish long-term persistent infection in brain cells. Three different neurologic complications result from interactions of measles virus with neural tissue. Acute postinfectious encephalitis encephalitis (ĕnsĕf'əlī`təs), general term used to describe a diffuse inflammation of the brain and spinal cord, usually of viral origin, often transmitted by mosquitoes, in contrast to a bacterial infection of the meninges , usually appearing 5-14 days after the rash, is thought to be a virus-induced autoimmune disease autoimmune disease, any of a number of abnormal conditions caused when the body produces antibodies to its own substances. In rheumatoid arthritis, a group of antibody molecules called collectively RF, or rheumatoid factor, is complexed to the individual's own gamma . Measles inclusion body encephalitis inclusion body encephalitis
A usually fatal disease that appears to result from persistent measles virus infection, causing inflammation in both the white and gray matter and characterized by the presence of nuclear inclusion bodies. , which occurs in immunocompromised immunocompromised /im·mu·no·com·pro·mised/ (-kom´pro-mizd) having the immune response attenuated by administration of immunosuppressive drugs, by irradiation, by malnutrition, or by certain disease processes (e.g., cancer). patients after a latent period latent period
1. The period elapsing between the application of a stimulus and the obvious response, such as the contraction of a muscle.
2. of 3-6 months, is believed to be a direct measles virus infection of neural tissue. The third form, subacute sclerosing panencephalitis (SSPE SSPE
subacute sclerosing panencephalitis
subacute sclerosing panencephalitis.
SSPE Subacute sclerosing panencephalitis, see there ), manifests 2-10 years after primary measles infection as a progressive and fatal chronic neurodegenerative disease Neurodegenerative disease
A disease in which the nervous system progressively and irreversibly deteriorates.
Mentioned in: Amnesia caused by persistent defective measles virus in neurons and oligodendrocytes. SSPE develops with high titers of anti-measles antibodies both in cerebrospinal fluid cerebrospinal fluid (CSF)
Clear, colourless liquid that surrounds the brain and spinal cord and fills the spaces in them. It helps support the brain, acts as a lubricant, maintains pressure in the skull, and cushions shocks. (CSF Cerebrospinal Fluid (CSF) Analysis Definition
Cerebrospinal fluid (CSF) analysis is a laboratory test to examine a sample of the fluid surrounding the brain and spinal cord. ) and serum, which seem unable to eliminate measles virus from the brain (3).
Although measles virus is serologically monotypic monotypic
said of a genus with only one species. , genetic variability has defined eight clades, including 20 genotypes and a putative new genotype that are geographically and temporally restricted (4). Evidence does not indicate that wild-type measles virus strains differ in terms of either pathogenesis or neurovirulence. Measles virus recovered from patients with SSPE differs from wild-type viruses in a number of mutations that mainly affect the matrix, hemagglutinin hemagglutinin /he·mag·glu·ti·nin/ (-gloo´ti-nin) an antibody that causes agglutination of erythrocytes.
cold hemagglutinin one which acts only at temperatures near 4° C. (H), nucleocapsid nucleocapsid /nu·cleo·cap·sid/ (noo?kle-o-kap´sid) a unit of viral structure, consisting of a capsid with the enclosed nucleic acid.
n. (N), and fusion genes. The matrix accumulates the highest level of mutations in the entire open reading frame; by contrast, the N is modified in the carboxyl carboxyl /car·box·yl/ (kahr-bok´sil) the monovalent radical —COOH, occurring in those organic acids termed carboxylic acids.
n. terminus, and the H has biased hypermutation in a limited region (5,6). Despite the paucity of studies in molecular epidemiology molecular epidemiology Molecular medicine An evolving field that combines the tools of standard epidemiology–case studies, questionnaires and monitoring of exposure to external factors with the tools of molecular biology–eg, restriction endonucleases, of SSPE, measles virus sequences obtained from brain tissues are homologous to the genotype circulating at the time of primary exposure to measles virus (7).
We studied eight children who had measles as infants during the 1998 measles outbreak in Argentina and in whom SSPE developed 4 years later. We report the genetic characterization of brain tissue associated measles virus from three of these patients.
Diagnosis of SSPE was based on Dyken's criteria, which include progressive cognitive decline and stereotypical myoclonus myoclonus /my·oc·lo·nus/ (mi-ok´lo-nus) shocklike contractions of a muscle or a group of muscles.myoclon´ic
essential myoclonus , characteristic electroencephalogram electroencephalogram /elec·tro·en·ceph·a·lo·gram/ (EEG) (-en-sef´ah-lo-gram?) a recording of the potentials on the skull generated by currents emanating spontaneously from nerve cells in the brain, with fluctuations in potential seen as (EEG EEG: see electroencephalography. ) changes, raised CSF globulin globulin, any of a large family of proteins of a spherical or globular shape that are widely distributed throughout the plant and animal kingdoms. Many of them have been prepared in pure crystalline form. levels without pleocytosis pleocytosis /pleo·cy·to·sis/ (ple?o-si-to´sis) presence of a greater than normal number of cells in cerebrospinal fluid.
n. , raised CSF measles antibody titers, and typical histopathologic findings in brain biopsy materials (8).
Antimeasles immunoglobulin (Ig) G antibodies in CSF and serum samples were assessed by using an automated qualitative enzyme-linked fluorescent immunoassay Immunoassay
An assay that quantifies antigen or antibody by immunochemical means. The antigen can be a relatively simple substance such as a drug, or a complex one such as a protein or a virus. (bioMerieux, Marcy l'Etoile, France) and a quantitative indirect immunofluorescence test (Bion, Des Plaines, IL). In three patients, measles virus RNA RNA: see nucleic acid.
in full ribonucleic acid
One of the two main types of nucleic acid (the other being DNA), which functions in cellular protein synthesis in all living cells and replaces DNA as the carrier of genetic was isolated from a punch of white matter obtained in the course of Ommaya reservoir implantation at SSPE onset. RNA was purified by the guanidinium-thiocyanate-phenol-chloroform method, and genetic characterization of measles virus was performed by sequencing the 450 nt from the carboxyl terminus of nucleoprotein nucleoprotein
Macromolecular complex consisting of a protein linked to a nucleic acid, either DNA or RNA. The proteins that combine with DNA are generally of characteristic types called histones and protamines. (N) gene and a 377-bp fragment of the H gene (9). Viral fragments were reverse-transcribed with omniscript and sensiscript enzymes, and amplified with Hot Start Taq DNA Polymerase (QIAGEN GmbH, Hilden, Germany). Purified polymerase chain reaction polymerase chain reaction (pŏl`ĭmərās') (PCR), laboratory process in which a particular DNA segment from a mixture of DNA chains is rapidly replicated, producing a large, readily analyzed sample of a piece of DNA; the process is products were labeled with DyET terminators and analyzed in an automatic capillary DNA sequencer (Amersham Biosciences, Piscataway, NJ). Comparisons were made with reference measles virus strains (4). Amino acid sequences were inferred. Nonsynonymous versus synonymous mutations ([omega]) and transitions versus transversions ([kappa]) ratios were calculated. Sequences were aligned with ClustalX software, while phylogenetic analysis was performed by distance methods with Phylip software package v. 3.5c (10,11). Sequences derived from this study were submitted to GenBank.
Clinical, epidemiologic, and laboratory findings of eight SSPE patients are described in the Table. Mean age at SSPE onset was 54 months (range 40-75 months), and the mean lag period was 48 months (range 33-68 months). Most patients (six of eight) resided in the greater Buenos Aires metropolitan area, one from the northeastern region mad the other from the northwestern region. All patients met at least clinical, EEG, and CSF antibody titer criteria defined by Dyken (8). In particular, patient 4 (at 6 months of age) had a clinical diagnosis of measles in September 1998 during the outbreak. Six months later, the patient received Measles Mumps Rubella rubella or German measles, acute infectious disease of children and young adults. It is caused by a filterable virus that is spread by droplet spray from the respiratory tract of an infected individual. (MMR MMR measles-mumps-rubella (vaccine); see measles, mumps, and rubella vaccine live, under vaccine.
measles, mumps, rubella vaccine ) vaccine according to the official immunization immunization: see immunity; vaccination. schedules. For patient 5, clinical diagnosis of measles was made at 10 months of age in September 1998 during the outbreak. At that time, he also had varicella varicella: see chicken pox. ; 2 months later, the patient received the MMR vaccine. Patient 6 was born in November 1997 and had no previous history of measles infection. She also received antimeasles vaccine at 6 months of age during the measles outbreak when the vaccination age was lowered.
The 450 nt from the carboxyl terminus of N gene and a 377-bp segment from H gene from three SSPE cases were analyzed and amino acid sequences were inferred. When compared to Edmonston strain, not only were a higher number of mutations found in N gene (36 vs. 19) but also more replacement changes (18 vs. 12) and a higher [kappa] ratio (2.1 vs. 1.2) as compared to H gene. However, we compared the [omega] ratio and found it to be higher for H gene (1.7 vs. 1). Fixed replacements were detected at position 357 in H protein and at position 467 in N protein. Variability was detected in both genes. Changes found in SSPE samples related to D6 genotype, and the consensus sequence from last Argentine outbreak are summarized in Figure 1.
[FIGURE 1 OMITTED]
Distance methods were applied, and the matrix rendered similar results for both analyzed genes. The tree was built with measles virus genotype reference strains and Argentine strains previously characterized from 1991 and 1998 outbreaks. Phylogenetic relationships clustered the three SSPE strains with the wild-type D6 genotype. SSPE samples were strongly associated with wild-type D6 samples from the 1998 outbreak, supported by a bootstrap See boot.
(operating system, compiler) bootstrap - To load and initialise the operating system on a computer. Normally abbreviated to "boot". From the curious expression "to pull oneself up by one's bootstraps", one of the legendary feats of Baron von Munchhausen. value of 100 out of 100 pseudoreplicates done. Divergence from genotype D6 (N J-1 strain) was <2.2% in the N gene and <2.4% in the H gene. The unrooted tree for the carboxyl terminus of N gene was plotted (Figure 2).
[FIGURE 2 OMITTED]
The measles vaccine was included in the regular immunization schedule in Argentina in 1978. Despite vaccination, several disease outbreaks have occurred (12). Although we had previously performed a thorough molecular description of acute measles outbreaks, genetic characterization of SSPE has not yet been reported in Argentina (9).
SSPE results in widespread destruction of brain tissue, including both gray and white matter. Infectious virus likely reaches the brain at the time of the original systemic spread of measles virus, where the virus becomes clonal, disseminating gradually throughout the nervous system from the point of entry (13). High levels of antimeasles antibodies are found both in serum and CSF, and their relative titers in the two compartments indicate intrathecal intrathecal /in·tra·the·cal/ (-the´k'l) within a sheath; through the theca of the spinal cord into the subarachnoid space.
Intrathecal synthesis of immunoglobulins.
Measles virus in SSPE is characterized by a low expression of viral envelope proteins as a result of mutational events. Among such proteins, H is an attachment protein that mediates binding to cells and contributes to cell-to-cell fusion. The V3571 mutation was one of the fixed changes that we had detected in the 1998 outbreak, but one of the SSPE cases (SSPE5) had a nonconservative V357S change at the same position (from hydrophobic to polar without charge) (9). This finding indicates that this particular position may be under strong positive selection supported by a high [omega]=1.7 and a low [kappa]=1.2. Although this fragment is a relatively small portion of the H gene, it contains a major antigenic surface determinant (aa368-396), which may he relevant for neurovirulence, as well as three linear epitopes containing conserved cysteines 381, 386, and 396. SSPE5 presented 5 replacement changes; one shared with SSPE6 (P368R, D374E, K375Q, Q384H, and P397S) (14,15).
On the other hand, the N protein is more closely linked to viral protein interactions and thus has less constraints to vary as demonstrated by a higher [kappa] (2.1) and lower [omega] (1) denoting neutral selection. Nevertheless, the B-cell epitope epitope: see immunity. (aa457-476) showed the conservative L467P change in SSPE samples as well as in 1998 outbreak samples, differing from the D6 reference strain (NJ-1) (16).
Molecular data from the 1998 Argentine outbreak showed that the virus belonged to the D6 genotype and that analyzed regions were highly homogeneous and almost identical to other D6 strains isolated in South America (9).
Accordingly, a single chain of transmission could be responsible for the spread of the genotype from European countries to Brazil and then to Argentina (17). The last Argentine outbreak began in July 1997 in the northeastern region of the country, bordering on Brazil; had its peak in greater Buenos Aires metropolitan area in July 1998; and ended in the northwestern region bordering on Bolivia in May 1999. For that reason, a displacement in time of acute measles and SSPE onset can be observed in SSPE3 and SSPE7.
Children in whom SSPE developed were born during the last measles outbreak and reached 6 months of age when the outbreak was at its peak. They acquired measles when they were 8 months of age (range 6-10 months), and SSPE was not detected among patients >1 year of age at the time of acute infection; however, underdiagnosis is a permanent challenge. Time lag between acute and SSPE 3 onset was approximately 4 years, according to the reported data, but the rate for developing SSPE was higher than previously described (8).
Phylogenetic analysis of three SSPE cases from the last outbreak clustered with D6 genotype that circulated in Argentina in 1998. Although the original sequence of the wild-type virus that caused acute infection is unknown, we have a consensus sequence that summarizes the outbreak; therefore, we infer that changes may have occurred since then and contributed to the development of SSPE. Although all three patients had been immunized according to the schedule, vaccinal strains were not detected in brain tissue. These results agree with those recently reported for SSPE patients in the United Kingdom and Papua, New Guinea (18,19). Our data show that these three patients had been infected with wild-type circulating D6 virus before immunization. This primary measles virus infection in nonimmunized infants may be the leading cause of the high rate of SSPE inferred from our data. After brain tissues of deceased adults were randomly autopsied, Lawrence et al. raised the possibility that brain measles infection does not invariably in·var·i·a·ble
Not changing or subject to change; constant.
in·vari·a·bil lead to neurologic disease caused by measles virus. Therefore, neurologic disease mediated by measles virus may depend on the primary infection age (20). Although the basis for measles-associated neurologic disease is unclear and more thorough molecular studies need to be performed, our findings contribute to worldwide efforts in molecular characterization of SSPE strains and aim to increase awareness among physicians to improve diagnosis at early stages.
Table. Clinical, epidemiologic, and laboratory findings for eight pediatric subacute sclerosing panencephalitis (SSPE) patients (a) Patient SSPE1 SSPE2 SSPE3 Date of birth Jan-98 Feb-98 Jul-98 Date of measles disease Sep-98 Sep-98 May-99 Date of SSPE onset May-01 Dec-Ol Feb-02 Geographic location GBA GBA NW CSF antibody titers 1:1600 1:1600 1:3200 Serum antibody titers >1:3200 >1:3200 1:12800 Initial diagnosis Progressive Acute Progressive myoclonic dissemina- myoclonic epilepsy ted ence- epilepsy phalo- myelitis Patient SSPE4# SSPE5# SSPE6# Date of birth Mar-98 Nov-97 Nov-97 Date of measles disease Sep-98 Sep-98 N/A Date of SSPE onset Jun-02 Aug-02 Sep-02 Geographic location GBA GBA GBA CSF antibody titers 1:3200 1:400 1:400 Serum antibody titers >1:3200 >1:3200 1:12800 Initial diagnosis Neuronal Lennox- Progressive ceroid Gastaut myoclonic lipofucsi- syndrome atonic nosis epilepsy Patient SSPF7 SSPE8 Date of birth Sep-96 Nov-97 Date of measles disease Jul 97 Jul-98 Date of SSPE onset Jan-03 Feb-03 Geographic location NE GBA CSF antibody titers 1:1600 1:400 Serum antibody titers N/A 1:400 Initial diagnosis Chorioreti- Ataxia nitis (a) Molecular studies were done for SSPE patients highlighted in #. N/A, not available; GBA, greater Buenos Aires metropolitan area; NW, northwestern region from Argentina; NE, northeastern region from Argentina; CSF cerebrospinal fluid. Figure 1. Replacement changes found in N and H genes from sub- acute sclerosing panencephalities patients. Comparisons were made with D6 genotype reference strain (New Jersey, USA/94/1). Sample Buenos Aires.ARG/21.98 was taken as a consensus sequence for the 1998 Argentine outbreak (ARG21.98). Numbers indicate the position in A-nucleoprotein and B-hemagglutin pro- tein, respectively. Dots designate the same residue as genotype D6. Nonsilent changes are represented by single letter amino acid code. Antigenic sites are underlined. A-Nucleoprotein 346 356 366 A SMGGLNFGRS YFDPAYFRLG QEMVRRSAGK D6 SSPE1 ---------- ---------- ---------- SSPE2 ---------- SSPE3 R A 406 416 426 A ISRAVGPRQA QVSFLHGDQS ENELPRLGGK D6 G SSPE1 PF G SSPE2 G SSPE3 G 466 476 486 A HLPTGTPLDI DTASESSQDP QDSRRSADAL D6 S T L SSPE1 P S T L SSPE2 P S T L SSPE3 P S S T L B-Hemagglutinin 281 291 301 A SNDLSNCMVA LGELKLAALC HGEDSITIPY D6 F SSPE1 SSPE2 SSPE3 - F 341 351 361 A TDDPVIDRLY LSSHRGVIAD NQAKWAVPTT D6 I SSPE1 I SSPE2 S R SSPE3 I P A-Nucleoprotein 376 386 396 A VSSTLASELG ITAEDARLVS EIAMHTTEDK D6 R SSPE1 ---------- ------- R SSPE2 N S R SSPE3 S R 436 446 456 A EDRRVKQSRG EARESYRETG PSRASDARAA D6 A D S SSPE1 A S SSPE2 A S SSPE3 A S 496 506 516 A LRLQAMAGIS EEQGSDTDTP IVYNDR D6 R SSPE1 -- SSPE2 R R SSPE3 R B-Hemagglutinin 311 321 331 A QGSGKGVSFQ LVKLGVWKSP TDMQSWVPLS D6 SSPE1 SSPE2 SSPE3 E 371 381 391 401 A RTDDKLRMET CFQQACKGKI QALCENPEWA PLKDNR D6 SSPE1 G SSPE2 EQ H S SSPE3 H
A.S.M. is a member of Comision de Investigaciones Cientificas de la Provincia de Buenos Aires (CIC CIC
circulating immune complexes.
CIC Circulating immune complexes. See Immune complexes. ). P.R.B. and M.V. are Fellows from the National Council of Investigation and Technology (CONICET CONICET Consejo Nacional de Investigaciones Científicas Y Técnicas (National Council for Science and Technology, Argentina) ). The Virology virology, study of viruses and their role in disease. Many viruses, such as animal RNA viruses and viruses that infect bacteria, or bacteriophages, have become useful laboratory tools in genetic studies and in work on the cellular metabolic control of gene expression Laboratory at Dr. R. Gutierrez Children's Hospital is the Reference Laboratory for the National Measles Elimination Program of Buenos Aires City Hall (GCBA GCBA Gobierno de la Ciudad de Buenos Aires (Buenos Aires, Argentina)
GCBA Genesee County Bar Association (Flint, Michigan)
GCBA Green Country Bluegrass Association (Oklahoma) ).
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(20.) Lawrence DMP DMP Dossier Médical Personnel (France)
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DMP Dynamic Multi-Pathing , Vaughn MM, Belman AR, Cole JS, Rall GF. Immune response-mediated protection of adult but not neonatal mice from neuron-restricted measles virus infection and central nervous system disease. J Virol 1999;73:1795-801.
Paola Roxana Barrero, * Jorge Grippo, * Mariana Viegas, * and Alicia Susana Mistchenko *
* Hospital de Ninos Dr. Ricardo Gutierrez, Buenos Aires, Argentina
Ms. Barrero has a fellowship from the National Council of Investigation and Technology (CONICET) in the virology laboratory at the Dr Ricardo Gutierrez Children's Hospital, Buenos Aires, Argentina. Her work is focused on molecular epidemiology of emerging and respiratory viruses.
Address for correspondence: Alicia S. Mistchenko, Laboratorio de Virologia, Hospital de Ninos Dr. Ricardo Gutierrez, Gallo 1330 (1425) Buenos Aires, Argentina; fax: 54-11-49626770; email: virologia @velocom.com.ar