Guillain-Barre syndrome, greater Paris area.We studied 263 cases of Guillain-Barre syndrome Guil·lain-Bar·ré syndrome n. See acute idiopathic polyneuritis. from 1996 to 2001, 40% of which were associated with a known causative agent, mainly Campylobacter jejuni Campylobacter jejuni Vibrio jejuni, Campylobacter fetus ssp jejuni A curved or spiral gram-negative bacillus with a single polar flagellum Epidemiology Linked to contact with domestic and farm animals, unpasteurized milk, primates, day care (22%) or cytomegalovirus cytomegalovirus (sī'təmĕg'əlōvī`rəs), member of the herpesvirus family that can cause serious complications in persons with weakened immune systems. (15%). The cases with no known agent (60%) peaked in winter, and half were preceded by respiratory infection Noun 1. respiratory infection - any infection of the respiratory tract respiratory tract infection infection - the pathological state resulting from the invasion of the body by pathogenic microorganisms , influenzalike syndrome, or gastrointestinal illness. ********** Guillain-Barre syndrome (GBS See GB/sec. ) is a state of acute flaccid paralysis Flaccid paralysis Paralysis characterized by limp, unresponsive muscles. Mentioned in: Botulism flaccid paralysis Neurology Paralysis characterized by complete loss of muscle tone and tendon reflexes. Cf Spastic paralysis. thought, in most cases, to result from an aberrant immune response immune response n. An integrated bodily response to an antigen, especially one mediated by lymphocytes and involving recognition of antigens by specific antibodies or previously sensitized lymphocytes. triggered by microbial microbial pertaining to or emanating from a microbe. microbial digestion the breakdown of organic material, especially feedstuffs, by microbial organisms. infections (1). Studies in Western countries have reported evidence of recent infection with Campylobacter jejuni in 15% to 40% of GBS cases and with cytomegalovirus (CMV CMV cytomegalovirus. CMV abbr. 1. controlled mechanical ventilation 2. cytomegalovirus Cytomegalovirus (CMV) ) in 5% to 20% of cases (1-5). Recent infection with Epstein-Barr virus Epstein-Barr virus (EBV), herpesvirus that is the major cause of infectious mononucleosis and is associated with a number of cancers, particularly lymphomas in immunosuppressed persons, including persons with AIDS. (EBV EBV Epstein-Barr virus. EBV abbr. Epstein-Barr virus Epstein-Barr virus (EBV) A virus in the herpes family that causes mononucleosis. ) or Mycoplasma pneumoniae Mycoplasma pneu·mo·ni·ae n. A microorganism causing primary atypical pneumonia in humans. was less frequent (1%-2% each) (1-5). No agent was identified in 60% to 70% of cases, although the patients often had a history of respiratory or gastrointestinal infection (1,2). Previous studies have failed to identify any clear seasonal distribution of GBS cases ill Europe and North America North America, third largest continent (1990 est. pop. 365,000,000), c.9,400,000 sq mi (24,346,000 sq km), the northern of the two continents of the Western Hemisphere. . It has been suggested that this failure to demonstrate seasonality in GBS is because most prevalent antecedent ANTECEDENT. Something that goes before. In the construction of laws, agreements, and the like, reference is always to be made to the last antecedent; ad proximun antecedens fiat relatio. infections have inverse seasonal distributions (6). We tested this hypothesis to provide new insight into infectious agents associated with GBS in Western countries. The Study All GBS patients admitted to the medical intensive care unit of Raymond Poincare Hospital in Garches, France, from January 1996 to December 2001 were included in the study. GBS was diagnosed according to according to prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. the criteria of Asbury and Cornblath (7). The following data were collected at the time of hospital admission: time from onset of neurologic signs of GBS to admission; history of infections in the 2 months preceding the onset of neurologic signs: and time from the infectious event to onset of neurologic signs. Serum samples were collected at hospital admission. Serum antibodies against C. jejuni and M. pneumoniae M. pneumoniae, n a species of Mycoplasma causing mycoplasma pneumonia, which is characterized by symptoms of an upper respiratory infection with a dry cough and fever. were assayed with complement fixation tests (Institut Virion virion Entire virus particle, consisting of an outer protein shell (called a capsid) and an inner core of nucleic acid (either RNA or DNA). The core gives the virus infectivity, and the capsid provides specificity (i.e., determines which organisms the virus can infect). , Wurzburg, Germany); cutoff titers (C. jejuni 20; M. pneumoniae 80) were selected to give >95% specificity on the basis of data provided by the manufacturer. Serum samples were tested for immunoglobulin M immunoglobulin M n. Abbr. IgM The class of antibodies found in circulating body fluids and the first antibodies to appear in response to an initial exposure to an antigen. (IgM) and IgG antibodies to CMV with the miniVIDAS system (bioMerieux, Marcy l'Etoile, France). IgG avidity avidity /avid·i·ty/ (ah-vid´i-te) 1. the strength of an acid or base. 2. in immunology, an imprecise measure of the strength of antigen-antibody binding based on the rate at which the complex is formed. Cf. was measured in samples positive for IgM by using the Enzygnost anti-CMV/IgG test (Dade Behring S.A., Paris la Defense Paris La Defense - Une Ville En Concert was a concert held by musician Jean Michel Jarre on the district of La Defense Paris on Bastille Day, July 14, 1990. About 2,5 million people standing in front of the pyramidical stage all the way down to the Arc de Triomphe witnessed this , France) and 8 mol/L urea. Recent CMV infection was identified by detection of IgM with IgG avidity <35% (8). Serum antibodies against EBV were detected with commercial dot blot Dot blot (or Slot blot) is a technique in molecular biology used to detect biomolecules. It replaces either northern blot, Southern blot or western blot. In dot blot the biomolecules to be detected are not separated by chromatography. tests (ImmunoDOT EBV MONO M and G kits, GenBio, San Diego San Diego (săn dēā`gō), city (1990 pop. 1,110,549), seat of San Diego co., S Calif., on San Diego Bay; inc. 1850. San Diego includes the unincorporated communities of La Jolla and Spring Valley. Coronado is across the bay. , CA, USA). Recent EBV infection was identified by detecting IgM antibodies to viral capsid capsid /cap·sid/ (kap´sid) the shell of protein that protects the nucleic acid of a virus; it is composed of structural units, or capsomers. cap·sid n. antigen. IgM and IgG antibodies against gangliosides GM1 and GM2 were identified by an enzyme 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. (GanglioCombi, Buhlmann Laboratories AG, Schonenbuch, Switzerland) and an imlnunodot blot assay (9). Statistical analyses were performed with the R 2.0.1 statistical package (R Development Core Team, Vienna, Austria). Groups were compared in pairs, and the Hochberg method for multiple testing was used to correct p values (10). Categorical variables were compared by Fisher exact test, and continuous variables were compared by Student t test or Wilcoxon rank sum test. Seasonal trends for GBS cases were analyzed by using the method of Jones et al. (11). The number of harmonics (seasonality periods) was determined by using the Akaike information criterion Akaike's information criterion, developed by Hirotsugu Akaike under the name of "an information criterion" (AIC) in 1971 and proposed in Akaike (1974), is a measure of the goodness of fit of an estimated statistical model. It is grounded in the concept of entropy. . All tests were 2-tailed, and a p value <0.05 was considered significant. During the study period, 279 consecutive patients with GBS were admitted to our center. Sixteen patients were excluded because of missing clinical data or serum samples; 263 were included in the study. On the basis of an annual incidence of 1.2 to 1.9 GBS cases per 100,000 persons (12) in a population of 10.952 million people (13), we estimated that 130-210 GBS cases occurred annually in the greater Paris area during the study period. Thus, this study included 20%-30% of all estimated GBS cases in this area. We observed serologic se·rol·o·gy n. pl. se·rol·o·gies 1. The science that deals with the properties and reactions of serums, especially blood serum. 2. evidence of recent infection with C. jejuni in 58 patients (21.9%), CMV in 40 (15.1%) patients, M. pneumoniae in 6 (2.3%) patients, and EBV in 3 (1.15%) patients. Recent infection with C. jeitmi and CMV was observed in 1 patient. Thus, 106 cases (40%) had [greater than or equal to] 1 known agent of GBS (known agent group), and 157 cases (60%) had no known agent (unknown agent group) (Table). Most patients in the C. jejuni group were male, were [greater than or equal to] 50 years of age, had a history of gastrointestinal illness (Figure 1), and exhibited a severe motor form of GBS with serum IgG antibodies against ganglioside ganglioside /gan·glio·side/ (gang´gle-o-sid) any of a group of glycosphingolipids found in the central nervous system tissues and having the basic composition ceramide-glucose-galactose-N -acetylneuraminic acid. GM1. Patients in the CMV group were significantly younger (p<0.0001), more likely to have respiratory or influenzalike symptoms than gastrointestinal symptoms (p<0.0001) before the onset of GBS symptoms (Figure 1), and showed a longer time from first neurologic signs to hospital admission (p = 0.048). These patients rarely showed a pure motor form of GBS (p = 0.037) and frequently had IgM antibodies against GM2 but did not have IgG antibodies against GM 1 (p<0.0001). [FIGURE 1 OMITTED] Patients in the unknown agent group were older than those in the CMV group (p<0.0001), less likely to have had a history of infectious events than patients in the C. jejuni group (p = 0.0048), and had a significantly different antiganglioside response than those in C. jejuni and CMV groups (p<0.0001 in each case) (Table). The unknown agent group had a higher proportion of patients with gastrointestinal illness than did the CMV group (p = 0.045) and a higher proportion of patients with respiratory tract respiratory tract n. The air passages from the nose to the pulmonary alveoli, including the pharynx, larynx, trachea, and bronchi. Respiratory tract or influenzalike symptoms than the C. jejuni group (p 0.0024) (Figure 1). No seasonal variation was found for all patients combined (data not shown). However, this apparent absence of variation masked a substantial seasonal difference for the known agent and unknown agent groups. In the known agent group, 60% of cases occurred in spring and summer; only 16% occurred in winter. In the unknown agent group, only 17% of cases occurred in summer; 37% occurred in winter. We used the method of Jones et al. (11) to test the seasonality of incidence. No seasonality was detected for the groups all cases, known agent, and C. jejuni (Figure 2). For the unknown agent group, a model with 1 harmonic (annual seasonality) gave a significantly better fit than a model without harmonics (p = 0.0089, by likelihood ratio test); additional harmonics did not improve the fit of the model. Since no significant linear trend was found (p = 0.49), this element was removed for model prediction. This best-fit, single-harmonic model indicated that incidence was highest at the beginning of February and lowest at the beginning of August (Figure 2). [FIGURE 2 OMITTED] Conclusions This study provides new data about GBS patients not associated with known etiologic agents, which account for most patients in Western Europe Western Europe The countries of western Europe, especially those that are allied with the United States and Canada in the North Atlantic Treaty Organization (established 1949 and usually known as NATO). (2,14). We have shown that GBS cases of unknown cause were more common in winter, with a peak incidence at the beginning of February. Moreover, in ~50% of the patients, GBS symptoms were preceded by respiratory infection, influenzalike syndrome, or gastrointestinal illness. Together with the seasonality of cases, this finding suggests the involvement of winter infectious agents, probably respiratory or enteric viruses. Acknowledgments We thank Isabelle Senegas for assistance and Marie-Helene Canneson for technical assistance. This work was supported by the Laboratoire Francais du Fractionnement et des Biotechnologies. Dr Sivadon-Tardy is a microbiologist at Raymond Poincare Hospital in Garches, France. Her primary research interests are 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, and emerging and reemerging infectious diseases. References (1.) Hughes RA, Hadden RD, Gregson NA, Smith KJ. Pathogenesis of Guillain-Barre syndrome. J Neuroimmunol. 1999;100:74-97. (2.) Hadden RD, Karch H, Hartung HP, Zielasek J, Weissbrich B, Schubert J, et al. Preceding infections, immune factors, and outcome in Guillain-Barre syndrome. Neurology. 2001 ;56:758-65. (3.) Rees JH, Soudain SE, Gregson NA, Hughes RA. Campylobacter jejuni infection and Guillain-Barre syndrome. N Engl J Med. 1995;333:1374-9. (4.) Visser LH, van der Meche FG, Meulstee J, Rothbarth PP, Jacobs BC, Schmitz PI, et al. Cytomegalovirus infection Cytomegalovirus infection A common asymptomatic infection caused by cytomegalovirus, which can produce life-threatening illnesses in the immature fetus and in immunologically deficient subjects. and Guillain-Barre syndrome: the clinical, electrophysiologic, and prognostic features. Dutch Guillain-Barre Study Group. Neurology. 1996;47:668-73. (5.) Jacobs BC, Rothbarth PH, van der Meche FG, Herbrink P, Schmitz PI, de Klerk MA, et al. The spectrum of antecedent infections in Guillain-Barre syndrome: a case-control study case-control study, n an investigation employing an epidemiologic approach in which previously existing incidents of a medical condition are used in lieu of gathering new information from a randomized population. . Neurology. 1998;51:1110-5. (6.) Hughes RA, Rees JH. Clinical and epidemiologic features of Guillain-Barre syndrome. J Infect Dis. 1997; 176(Suppl 2):S92-8. (7.) Asbury AK, Comblath DR. Assessment of current diagnostic criteria for Guillain-Barre syndrome. Ann Neurol. 1990;27:S21-4. (8.) Grangeot-Keros L, Mayaux MJ, Lebon P, Freymuth F, Eugene G, Stricker R, et al. Value of cytomegalovirus (CMV) IgG avidity index for the diagnosis of primary CMV infection in pregnant women. J Infect Dis. 1997;175:944-6. (9.) Chabraoui F, Derrington EA, Mallie-Didier F, Confavreux C, Quincy C, Caudie C. Dot-blot immunodetection of antibodies against GM1 and other gangliosides on PVDF-P membranes. J Immunol Methods. 1993;165:225-30. (10.) Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 1988;75:800-3. (11.) Jones RH, Ford PM, Hamman RF. Seasonality comparisons among groups using incidence data. Biometrics. 1988;44:1131-44. (12.) Hughes RA, Cornblath DR. Guillain-Barre syndrome. Lancet. 2005;366:1653-66. (13.) French Population Census. March 1999. The results. Paris: National Institute for Statistics and Economic Studies. Version 2.30.07. 2005 Dec 12 [cited 2006 Feb 6]. Available from http://www. recensement.insee.fr/RP99 (14.) Van Koningsveld R, van Doom PA, Schmitz PI, Ang CW, van der Meche FG. Mild forms of Guillain-Barre syndrome in an epidemiologic survey epidemiologic survey, n See research, epidemiologic survey. in The Netherlands. Neurology. 2000;54:620-5. Address for correspondence: Valerie Sivadon-Tardy, Laboratoire de Microbiologie, Hopital Raymond Poincare, 104 Blvd Raymond Poincare, CEDEX 92380, Garches, France; email: valerie.sivadon@rpc.ap-hopparis.fr Use of trade names is for identification only and does not imply endorsement by the Public Health Service or by the U.S. Department of Health and Human Services Noun 1. Department of Health and Human Services - the United States federal department that administers all federal programs dealing with health and welfare; created in 1979 Health and Human Services, HHS . Valerie Sivadon-Tardy, * David Orlikowski, * Fiore Rozenberg, ([dagger]) Christiane Caudie, ([double dagger]) Tarek Sharshar, * Pierre Lebon, ([dagger]) Djillali Annane, * Jean-Claude Raphael, * Raphael Porcher, ([section]) and Jean-Louis Gaillard * * Hopital Raymond Poincare, Garches, France; ([dagger]) Hopital Saint-Vincent-de-Paul, Paris, France; ([double dagger]) Hopital Neurologique et Neurochirurgical Pierre Wertheimer, Lyon, France; and ([section]) Hopital Saint-Louis, Paris, France
Table. Characteristics of patients with Guillain-Barre syndrome *
Campylobacter
Characteristic All patients jejuni
No. 263 58
Sex, no. (%)
Female 112 (43) 21 (36)
Male 151 (57) 37 (64)
Mean age, y (SD) 48.7 (18.3) 51.3 (19.4)
Median days from infectious event 8 (4-15) 7 (4-14.2)
to neurologic signs (IQR)
Median days from neurologic signs to 5.5 (3-9) 4 (2.5-7)
hospital admission (IQR)
Infectious event, no. (%)
None 99 (38) 13 (22)
[greater than or equal to] 1 164 (62) 45 (78)
Infectious event, no. (%)
GI 61 (37) 30 (67)
URTI 37 (23) 6 (13)
LRTI 29 (12) 2 (4)
Influenzalike 30 (18) 5 (11)
Others 16 (10) 2 (4)
Only motor symptoms, no. (%) 101 (39) 31 (54)
Mechanical ventilation, no. (%) 87 (333) 23 (40)
Antibodies to gangliosides, no. (%)
GM1 30 (13) 24 (44)
GM2 15 (6) 0
Characteristic CMV Unknown agent
No. 40 157
Sex, no. (%)
Female 22 (55) 66 (42)
Male 18 (45) 91 (58)
Mean age, y (SD) 35.9 (12.0) 51.2 (17.9)
Median days from infectious event 10 (4.5-18) 8 (5-15)
to neurologic signs (IQR)
Median days from neurologic signs to 7 (3-11) 6 (3-10)
hospital admission (IQR)
Infectious event, no. (%)
None 14 (35) 73 (47)
[greater than or equal to] 1 26 (65) 84 (53)
Infectious event, no. (%)
GI 3 (11) 27 (31)
URTI 9 (35) 21 (25)
LRTI 1 (4) 12 (14)
Influenzalike 6 (23) 18 (21)
Others 7 (27) 6 (7)
Only motor symptoms, no. (%) 11 (28) 57 (37)
Mechanical ventilation, no. (%) 15 (38) 43 (27)
Antibodies to gangliosides, no. (%)
GM1 0 5 (4)
GM2 15 (47) 0
p value p value
Characteristic ([dagger]) ([double dagger])
No.
Sex, no. (%) 0.53 0.31
Female
Male
Mean age, y (SD) 0.94 <0.0001
Median days from infectious event 0.45 0.55
to neurologic signs (IQR)
Median days from neurologic signs to 0.11 0.27
hospital admission (IQR)
Infectious event, no. (%) 0.0048 0.25
None
[greater than or equal to] 1
Infectious event, no. (%) 0.0049 0.026
GI
URTI
LRTI
Influenzalike
Others
Only motor symptoms, no. (%) 0.056 0.35
Mechanical ventilation, no. (%) 0.20 0.49
Antibodies to gangliosides, no. (%)
GM1 <0.0001 0.59
GM2 1.00 <0.0001
* CMV, cytomegalovirus; SD, standard deviation, IQR, interquartile
range; GI, gastrointestinal illness; URTI, upper respiratory tract
infection; LRTI, lower respiratory tract infection.
([dagger]) Adjusted for unknown agent versus C. jejuni.
([double dagger]) Adjusted for unknown agent versus CMV.
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