Regional Variation of Guillain-Barré Syndrome

Alex Y. Doets; Christine Verboon; Bianca van den Berg; Thomas Harbo; David R. Cornblath; Hugh J. Willison; Zhahirul Islam; Shahram Attarian; Fabio A. Barroso; Kathleen Bateman; Luana Benedetti; Peter van den Bergh; Carlos Casasnovas; Guido Cavaletti; Govindsinh Chavada; Kristl G. Claeys; Efthimios Dardiotis; Amy Davidson; Pieter A. van Doorn; Tom E. Feasby; Giuliana Galassi; Kenneth C. Gorson; Hans-Peter Hartung; Sung-Tsang Hsieh; Richard A.C. Hughes; Isabel Illa; Badrul Islam; Susumu Kusunoki; Satoshi Kuwabara; Helmar C. Lehmann; James A.L. Miller; Quazi Deen Mohammad; Soledad Monges; Eduardo Nobile Orazio; Julio Pardo; Yann Pereon; Simon Rinaldi; Luis Querol; Stephen W. Reddel; Ricardo C. Reisin; Nortina Shahrizaila; Soren H. Sindrup; Waheed Waqar; Bart C. Jacobs; the IGOS Consortium

Disclosures

Brain. 2018;141(10):2866-2877. 

In This Article

Materials and Methods

This study is registered at ClinicalTrials.gov with identifier: NCT01582763

Study Design

The IGOS study protocol has been described elsewhere (Jacobs et al., 2017). The current study was based on the analysis of the first 1000 included patients. Patients fulfilled diagnostic criteria for GBS or its variants and were included within 2 weeks from onset (Asbury and Cornblath, 1990; Sejvar et al., 2011b; Wakerley et al., 2014). Patients were enrolled between May 2012 and July 2015 from 135 active study sites in 18 countries across five continents. The study was approved by the review boards of Erasmus University Medical Centre, Rotterdam, The Netherlands, and the local institutional review boards of participating hospitals or universities. Written informed consent was obtained from all patients.

Data Collection

Data were collected regarding demography, antecedent events, and neurological symptoms and signs of GBS at study entry and at 1, 2, 4, 8, 13, 26 and 52 weeks (Jacobs et al., 2017). Muscle strength was recorded by the Medical Research Council (MRC) score (Kleyweg et al., 1991) and disability by the GBS disability score (Hughes et al., 1978). Presence of autonomic dysfunction, defined as cardiac, blood pressure, gastro-enteric, bladder, pupil, or other (e.g. excessive perspiration) abnormalities, was left to the decision of the treating physician. Results of routine CSF examination and nerve conduction studies (NCS) were collected. We defined an elevated CSF protein level as >0.45 g/l (Hadden et al., 2001; Jacobs et al., 2017). A cytoalbuminological dissociation was defined as a CSF cell count <50 cells/μl combined with a CSF protein level >0.45 g/l. To determine the electrophysiological subtype, we used raw data of the first NCS, local reference values, and an algorithm to classify each NCS into demyelinating, axonal, inexcitable, equivocal, or normal subtype, according to criteria of Hadden et al. (1998). Patients with axonal and demyelinating neuropathy were compared for each region, to specify previously reported differences between these subtypes.

Disease nadir was defined by the lowest MRC sum score during the first 4 weeks from study entry. When two visits had equal lowest MRC sum scores, the first visit score was used. Patients who had reached nadir before study entry and patients lost to follow-up in the first 4 weeks were excluded from the analysis of nadir.

Asymmetrical weakness was defined as a difference in MRC sum scores of ≥5 points between the right- versus left-sided muscles (Fokke et al., 2014).

Clinical variants were adopted from the reported variants at visit Week 2, substantiated by recorded data, and were defined as: (1) sensorimotor; (2) pure motor; (3) MFS or MFS-GBS overlap syndrome; and (4) other, which included pure sensory, ataxic, and pharyngeal-cervical-brachial (Wicklein et al., 1997; van den Berg et al., 2014; Wakerley et al., 2014; Willison et al., 2016).

Local treating physicians registered clinical fluctuations. We additionally checked the data for fluctuations defined as a deterioration in MRC sum score >5 points and/or a deterioration on the GBS disability scale ≥1 point(s) during two consecutive visits, not caused by non-GBS related complications, within the first year of follow-up. A deterioration on the GBS disability scale from 0 ('a healthy state') to 1 ('minor symptoms') was not considered a fluctuation. When MRC sum score, GBS disability score and information on clinical fluctuations were missing for two or more consecutive visits, the occurrence of a fluctuation was considered undeterminable.

When patients received multiple immunomodulating treatments (i.e. combinations of IVIg and plasma exchange), we used the first administered therapy for the treatment analysis.

The primary endpoints for clinical outcome were the ability to walk independently (GBS disability score ≤2) at 6 and 12 months. Patients who were lost to follow-up at or after 26 and 52 weeks, or who had a missed visit and were able to walk independently at the previous visit, were considered to have reached this endpoint.

Geographical Regions

To determine geographical influence on the variation of GBS, we subdivided patients into three different regions: 'Europe/Americas' (including Argentina, Belgium, Canada, Denmark, France, Germany, Greece, Italy, Spain, The Netherlands, UK, and USA), 'Asia' (including Japan, Malaysia, and Taiwan), and 'Bangladesh'. These regions were based on previously reported prevalences of clinical variants and electrophysiological subtypes of GBS, national income level (World Bank, 2017), availability or affordability of specific immunotherapy with standard of supportive care, and geographical location of the participating countries. Europe and Americas were initially considered two separate regions based on their geographical location, but were later combined because of great similarity of the other determinative variables. The Asian group consisted only of high-income countries with good quality medical services and availability of treatment. For this study, we excluded patients from Africa (n = 11) and Australia (n = 4) from the geographical analysis because of small patient numbers.

Statistical Analysis

We used SPSS Statistics 21.0 for data analysis. Continuous data are presented as medians with interquartile ranges (IQR) and dichotomized or categorical data as numbers and proportions. We used the Mann-Whitney U-test and Kruskal-Wallis test to compare continuous data, and the χ 2-test or Fisher's exact test to compare proportions. Kaplan-Meier analysis was used to present the proportion of participants able to walk independently during follow-up. A two-sided P-value < 0.05 was considered significant. P-values reflect comparisons of the three regions, unless stated otherwise.

Data Availability

Data collected in IGOS will be used initially for planned research projects conducted by the IGOS Consortium. Some data will be made available from the corresponding author, upon reasonable request. The data are not publicly available because they contain information that could compromise the privacy of our patients.

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