Frequency of exposure to arboviruses and characterization of Guillain Barré syndrome in a clinical cohort of patients treated at a tertiary referral center in Brasília, Federal District

Luíza Morais de Matos Ariely Teotonio Borges Aline Barbosa Palmeira Vinicius Moreira Lima Ernane Pires Maciel Rubens Nelson Morato Fernandez João Pedro Lima Mendes Gustavo Adolfo Sierra Romero About the authors

ABSTRACT

Background:

Guillian Barré syndrome (GBS) is an acute autoimmune polyradiculoneuropathy often associated with previous exposure to infectious agents.

Methods:

A clinical cohort of 41 patients with GBS admitted to the Base Hospital Institute of the Federal District between May 2017 and April 2019 was followed up for 1 year. Serological tests for arbovirus detection and amplification of nucleic acids using polymerase chain reaction for zika virus (ZIKV), dengue virus (DENV), and chikungunya virus (CHIKV) were performed.

Results:

The cohort consisted of 61% men with a median age of 40 years, and 83% had GBS-triggering events. A total of 54% had Grade 4 disability, 17% had Grade 3, 12% had Grade 2, 10% had Grade 5, and 7% had Grade 1. The classic form occurred in 83% of patients. Nerve conduction evaluations revealed acute demyelinating inflammatory polyneuropathy (51%), acute motor axonal neuropathy (17%), acute sensory-motor neuropathy (15%), and indeterminate forms (17%). Four patients were seropositive for DENV. There was no laboratory detection of ZIKV or CHIKV infection. Ninety percent of patients received human immunoglobulin. Intensive care unit admission occurred in 17.1% of the patients, and mechanical ventilation was used in 14.6%. One patient died of Bickerstaff’s encephalitis. Most patients showed an improvement in disability at 10 weeks of follow-up.

Conclusions:

GBS in the Federal District showed a variable clinical spectrum, and it was possible to detect recent exposure to DENV.

Keywords:
Guillain Barré Syndrome; Arbovirus; Dengue; Clinical cohort; Diagnosis; Prognosis

INTRODUCTION

Guillain Barré syndrome (GBS) comprises a group of heterogeneous disorders with acute onset and is one of the most common causes of acute flaccid paralysis worldwide. The main characteristic is bilateral muscle weakness associated with somatosensory changes, dysautonomia, hyporeflexia, and pain, reaching a nadir of severity in up to 4 weeks11. Van den Berg B, Walgaard C, Drenthen J, Fokke C, Jacobs BC, van Doorn PA. Guillain Barré syndrome: pathogenesis, diagnosis, treatment and prognosis. Nat Rev Neurol. 2014;10(8):469-82.. GBS occurs via activation of autoimmunity against the peripheral nervous system after various stimuli, often of infectious origin22. Wachira VK, Peixoto HM, de Oliveira MRF. Systematic review of factors associated with the development of Guillain-Barré syndrome 2007-2017: what has changed? Trop Med Int Health. 2019;24(2):132-42.,33. Malek E, Salameh J. Guillain-Barre Syndrome. Semin Neurol. 2019;39(5):589-95.. Affected patients generally have a good prognosis and recover within weeks after the onset of symptoms. However, approximately 5% of patients die from complications, including respiratory failure, pneumonia, and arrhythmias44. Goodfellow JA, Willison HJ. Guillain-Barré syndrome: a century of progress. Nat Rev Neurol . 2016;12(12):723-31.,55. Peixoto HM, Romero GAS, de Araújo WN, de Oliveira MRF. Guillain-Barré syndrome associated with Zika virus infection in Brazil: a cost-of-illness study. Trans R Soc Trop Med Hyg. 2019;113(5):252-8.,66. Wachira VK, Nascimento GL, Peixoto HM, de Oliveira MRF. Burden of Disease of Guillain-Barré Syndrome in Brazil before and during the Zika virus epidemic 2014-2016. Trop Med Int Health . 2021 Jan;26(1):66-81..

GBS diagnosis is based on a combination of characteristics known as the Brighton criteria77. WHO: Identification and management of Guillain-Barré syndrome in the context of Zika virus Interim guidance; 2016.. There is a cerebrospinal fluid (CSF) pattern of the disease, which may be normal at the onset but exhibits an increase in total proteins with a normal nucleated cell count characterized by protein- or albumin-cytological dissociation88. Yuki N, Hartung HP. Guillian_Barré syndrome. New England Journal of Medicine. 2012; 366:2294-304..

GBS is classified into clinical variants, including classical GBS, pharyngo-cervico-brachial (FCB), paraparetic, facial diparesis form, Miller-Fisher syndrome (SMF), Bickerstaff encephalitis (BE), and overlaps between the variants99. Wakerley BR, Uncini A, Yuki N, GBS Classification Group. Guillain-Barré and Miller Fisher syndromes - new diagnostic classification. Nat Rev Neurol . 2014 Sep;10(9):537-44..

Nerve conduction (NEC) studies have revealed the following subtypes: acute demyelinating inflammatory polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute sensory-motor neuropathy (AMSAN), and indeterminate pattern1010. Grapperon AM, Berro M, Salort-Campana E, Verschueren A, Delmont E, Attarian S. GuillainBarré syndrome subtypes: A clinical electrophysiological study of 100 patients. Revue Neurologique (Paris). 2019;175(1-2):73-80..

Infectious and noninfectious environmental agents in genetically susceptible hosts trigger disease development. Zika virus (ZIKV) infection, a ribonucleic acid (RNA) flavivirus transmitted by mosquitoes of the genus Aedes, was identified as a potential trigger for GBS55. Peixoto HM, Romero GAS, de Araújo WN, de Oliveira MRF. Guillain-Barré syndrome associated with Zika virus infection in Brazil: a cost-of-illness study. Trans R Soc Trop Med Hyg. 2019;113(5):252-8.. ZIKV causes a self-limited disease that may be asymptomatic or present with skin rash, gastrointestinal disorders, fever, arthralgia, headache, conjunctivitis1111. Dejnirattisai W, Supasa P, Wongwiwat W, Rouvinski A, Barba-Spaeth G, Duangchinda T, et al. Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus. Nature Immunology. 2016; (9):1102-8., and occasionally congenital microcephaly, para-infectious, and post-infectious GBS1212. Pinto Junior VL, Luz K, Parreira R, Ferrinho P. Zika virus: A Review to clinicians. Acta Médica Portuguesa. 2015; 28(6):760-5.. An increased incidence of GBS was reported concomitantly with the ZIKV epidemic, and a relationship between arboviruses and GBS has been observed66. Wachira VK, Nascimento GL, Peixoto HM, de Oliveira MRF. Burden of Disease of Guillain-Barré Syndrome in Brazil before and during the Zika virus epidemic 2014-2016. Trop Med Int Health . 2021 Jan;26(1):66-81.. Encephalitis and GBS were also related to dengue virus (DENV) and chikungunya virus (CHIKV) progression, with long-term sequelae and expressive abnormalities in radiological examinations in patients with brain disorders1313. Pinheiro TJ, Guimarães LF, Silva MTT, Soares CN. Neurological manifestations of Chikungunya and Zika infections. Arquivos de Neuropsiquiatria 2016;74(11):937-43.,1414. Vanjare HA, Mannam P, Mishra AK, Karuppusami R, Carey RAB, Abraham AM, et al. Brain imaging in cases with positive serology for dengue with neurologic symptoms: A clinico-radiologic correlation. American Journal of Neuroradiology. 2018;39(4):699-703.,1515. Waterman SH, Margolis HS, Sejvar JJ. Surveillance for dengue and dengue-associated neurologic syndromes in the United States. American Journal of Tropical Medicine & Hygiene. 2015 May;92(5):996-8..

Treatment includes intravenous human immunoglobulin (IVIg) and plasmapheresis, which accelerate recovery1616. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2014 Sep 19;2014(9):CD002063..

Despite the increased rates of GBS associated with the ZIKV outbreak1717. Silva IRF, Frontera JA, Bispo de Filippis AM, Nascimento OJMD; RIO-GBS-ZIKV Research Group. Neurologic Complications Associated with the Zika Virus in Brazilian Adults. JAMA Neurology. 2017 Oct 1;74(10):1190-1198.,1818. Styczynski AR, Malta JMAS, Krow-Lucal ER, Percio J, Nóbrega ME, Vargas A, et al. Increased rates of Guillain-Barré syndrome associated with Zika virus outbreak in the Salvador metropolitan area, Brazil. PLoS Negl Trop Dis. 2017 Aug 30;11(8)., no studies have examined the clinical characterization of GBS and its long-term evolution in the Federal District, and no systematic investigation of exposure to arboviruses DENV, ZIKV, and CHIKV have been performed. Therefore, the present study aimed to describe a clinical cohort of patients with GBS treated at a tertiary-level referral center and explore the exposure to three arboviruses that circulate in a sympatric manner in the Federal District.

METHODS

The study was nested in the Zika and other Arbovirus Infections Cohort Studies initiative of the Center of Tropical Medicine of the University of Brasilia, within the framework of the research project Natural History of ZIKV Infection in the Federal District. This project was designed to analyze the clinical, epidemiological, and immunological data on ZIKV infection and other arboviruses in the general population, pregnant women, and live births in the Federal District in a scenario of sympatric circulation of DENV and CHIKV viruses and high vaccination coverage against yellow fever.

The sample was a clinical cohort of patients admitted with suspected GBS at the Instituto Hospital de Base do Distrito Federal (IHBDF), a tertiary-level referral unit and the largest public hospital in the Federal District, from May 2017 to May 2019. Because GBS is a relatively rare clinical entity, the sample was defined for the universal patients who consulted for suspected clinical conditions of GBS and were referred to the IHBDF neurological emergency unit from May 2017 to April 2019.

The level of diagnostic certainty was based on clinical and laboratory data classified from 1 to 3 according to the case definitions of the Brighton Collaboration in the context of the Zika virus Interim Guidance (WHO)77. WHO: Identification and management of Guillain-Barré syndrome in the context of Zika virus Interim guidance; 2016.. The following inclusion criteria were used for the cases: GBS diagnosis according to the Brighton diagnostic criteria, onset of symptoms within 4 weeks preceding the consultation and signing the informed consent form (ICF). In addition, cases with a confirmed etiology other than GBS were excluded. The clinical variants of GBS were Miller Fisher syndrome, pharyngeal-cervical-brachial weakness, paraparetic GBS, bifacial weakness with paresthesia, Bickerstaff’s brainstem encephalitis with subtypes, and possible overlaps (adapted Wakerley classification)99. Wakerley BR, Uncini A, Yuki N, GBS Classification Group. Guillain-Barré and Miller Fisher syndromes - new diagnostic classification. Nat Rev Neurol . 2014 Sep;10(9):537-44..

The collected data included epidemiological characteristics, prodromal symptoms, diagnostic tests for GBS, clinical characteristics and signs of severity, treatment, and time to symptom improvement. The evaluation consisted of interviews, physical examination, and neurological evaluation using the standardized GBS Outcome Study-ZIKA (IGOS)1919. Jacobs BC, van den Berg B, Verboon C, Chavada G, Cornblath DR, Gorson KC, et al. International Guillain-Barré Syndrome Outcome Study: protocol of a prospective observational cohort study on clinical and biological predictors of disease course and outcome in Guillain-Barré syndrome. J Peripher Nerv Syst. 2017 Jun;22(2):68-76.,2020. IGOS-ZIKA©: Um estudo prospectivo para determinar a associação entre infecções por Zika vírus e a Síndrome de Guillain-Barre (SGB) em pacientes de áreas endêmicas para Zika, baseados no protocolo do Estudo Internacional de Prognóstico da SGB (IGOS), versão 2, 29 de fevereiro de 2016.. Aspects of the acute phase and progression of GBS, and the presence of signs and symptoms related to arboviruses, were evaluated in an interview. The physical examination included data on stance, gait assessment, muscle bulk, tone, limb strength and reflexes, coordination, posture, changes in sensory function, involvement of the cranial nerves, involvement of the autonomic system, severity indicators, intensive care unit (ICU) admission, mechanical ventilation, and complications. Previous potential triggering GBS events that occurred 4 weeks before neurological onsets, such as diarrhea, flu, vaccination, and symptoms related to infections by DENV, ZIKV, and CHIKV, such as exanthema, arthralgia, fever, and diarrhea, were also recorded. A neurologist performed clinical examinations upon admission and 1-2, 4-8, 13, 26, and 52 weeks after admission.

The patients were subjected to the following examinations during hospitalization: CSF analysis (cytology, protein); serological tests for arbovirus detection; and amplification of nucleic acids using polymerase chain reaction (PCR) for ZIKV, DENV, and CHIKV in the CSF, serum, and urine samples. Briefly, the serological test was immunoglobulin M antibody capture enzyme-linked immunosorbent assay (MAC-ELISA), and the molecular test was real-time quantitative PCR (RT-qPCR) using the TaqMan® system with probes and primers with previously defined oligonucleotide sequences from a published Centers for Disease Control and Prevention (CDC) protocol2121. Kuno G, Gómez I, Gubler DJ. Detecting artificial anti-dengue IgM immune complexes using an enzyme-linked immunosorbent assay. Am J Trop Med Hyg. 1987; 36(1): 153-9. 2222. Johnson BW, Russell BJ, Lanciotti RS. Serotype-specific detection of dengue viruses in a fourplex real-time reverse transcriptase PCR assay. J Clin Microbiol. 2005; 43(10): 4977-83..

A nerve conduction study (NEC) included the following subtypes: acute demyelinating inflammatory polyneuropathy (AIPD), AMAN, AMSAN, and indeterminate pattern based on the Asbury and Cornblath criteria2323. Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barré syndrome. Ann Neurol. 1990;27 Suppl: S21-4.. During follow-up, clinical or laboratory data were obtained in addition to the electronic medical records used in the IHBDF and during the recent coronavirus disease 2019 (COVID-19) panic via a video conference.

The follow-up flow was as follows: admission and emergency care of the IHBDF by the neurology team on duty; performing the clinical diagnosis of GBS and requesting lumbar puncture to collect CSF for laboratory diagnosis of GBS; offer and signature of the TCLE; a collection of venous blood and urine samples; ordering tests of biological samples to the Central Laboratory of Public Health of the Federal District (LACEN DF); neurological evaluation using the standardized form GBS Outcome Study-ZIKA (IGOS) upon admission and at 1-2, 4-8, 13, 26, and 52 weeks; and performance of electroneuromyography during hospitalization in the neurology ward.

Data were recorded on the Redcap online platform and made available in Microsoft Excel spreadsheets. Categorical variables were analyzed as raw frequencies and proportions, and normally distributed continuous variables were expressed as means or medians, with the corresponding measures of dispersion. The frequency of arbovirus infection in the studied samples was expressed as a percentage. Survival analysis was performed using the Statistical Package for Social Sciences (SPSS) v. 21. Estimates were obtained using the Kaplan-Meier method. Survival rates were compared between groups using the log-rank test with a 5% significance level for decision making. The outcome of interest in the survival analysis was the improvement defined by the reducing at least one point in the classification of the degree of disability over the 52-week follow-up period. Participants who did not exhibit the outcome of interest until week 52 were censored and the time of the last evaluation performed during the follow-up period was used as a reference. The estimates of the time to outcome are expressed as medians with their respective 95% confidence intervals (CI). All analyses were performed using the International Business Machine (IBM) SPSS, version 21. The study followed the recommendations for research involving humans, including the Council National Health Board Resolution No. 466 of December 12, 2012 (DOU, 2013, Section 1. n°12) and the Declaration of Helsinki2424. WMA Declaration of Hensinki. Ethical Principles for Medical Research Involving Human Subjects. 9 de julho de 2018.. All the participants provided written informed consent. The research ethics committee of the Faculty of Medicine of the University of Brasília (CAAE 1.989.868) and the Foundation for Teaching and Research in Health Sciences/State Health Secretariat, Federal District (CAAE 1.910.150) approved this study.

RESULTS

Forty-eight patients were considered candidates as participants in the study. Seven candidates were excluded: five due to alternative diagnoses, one due to death before signing the ICF, and one who did not meet the Brighton criteria. Therefore, only 41 patients were included in this study. Table 1 describes the clinical and laboratory characteristics and assessment of nerve conduction upon admission, treatment provided, and observed complications during hospitalization.

TABLE 1:
Characteristics of 41 patients with GBS at admission treated at a tertiary referral center from May 2017 to April 2019 in the Federal District, Brazil.

Thirty-four patients (83%) had events prior to the onset of weakness that may have triggered GBS: 16 patients (39%) had an infection of the upper respiratory tract; 13 patients (32%) had gastroenteritis; patients (10%) had a recent vaccination (2 received a tetanus vaccine, 1 received an influenza vaccine, and 1 received a vaccine against hepatitis B); 7 patients (17%) had other events, including 1 pregnant patient, 1 patient in the puerperium, and 1 patient with dengue confirmed by serology before admission to the study, 2 patients had a rash, and 2 patients had myalgia and arthralgia. The median period between the event with triggering potential and the onset of weakness was 7 days.

The symptoms and exposure factors that suggested arbovirus infection were fever (32%), diarrhea (20%), skin rash or rash (7%), arthralgia (7%), and mosquito bite (5%). The "seasonal tropical climate" division of cases was 70% during the rainy season and 41% during the dry season.

The pain was reported by 46% of the patients during admission. Meningism was not observed in this study. The most affected sites were the legs (27%), dorsal region (29%), arms (22%), neck (7%), ventral region (5%), face (2%), and other sites (5%). Cranial nerve involvement was observed in 54% of the cases, of which 34% involved facial nerves, 29% involved bulbar nerves, 7% involved oculomotor nerves, and 7% involved other nerves.

Fifty-one percent of the patients had preserved cervical strength upon admission. Lower limb weakness was more severe than upper limb weakness. The paresis of the upper and lower limbs had a predominance of Grade 4 strength according to the Medical Research Council strength scale. Most patients had areflexia, and 54% had sensory deficits. The legs were most affected by sensory loss (46%), followed by the arms (22%) and trunk, vertex, and face (5%). Deficits in pain, vibration, and tactile sensitivity were equally prevalent in 27% of the patients. Ataxia was observed in only 15% of the patients tested (71%).

Autonomic dysfunction was present in 42% of the patients, with changes in blood pressure (20%), bladder dysfunction (17%), gastroenteric dysfunction (7%), and cardiac dysfunction (5%).

Eighty-three percent had the classic form without variants, 2% had FCB, 2% had SMF, 7% had SGB-SMF overlap, and 5% had SMF-FCB overlap. There were no cases of paraparetic GBS (Wakerley classification)99. Wakerley BR, Uncini A, Yuki N, GBS Classification Group. Guillain-Barré and Miller Fisher syndromes - new diagnostic classification. Nat Rev Neurol . 2014 Sep;10(9):537-44..

Thirty-nine patients underwent electromyography (EMG) during admission. AIDP was found in 53.8% of cases, AMAN in 23%, acute AMSAN in 20.5%, and an undetermined form in 2.5%.

Forty-one percent of the patients exhibited Grade 0 disability in their last evaluation (52 weeks) and showed complete improvement of symptoms after at least 1-year of follow-up (Figure 1). In addition, a significant decrease in disability was observed.

FIGURE 1:
Degree of disability observed upon admission and compared with the last follow-up evaluation (52 weeks) in patients with GBS treated at the IHBDF from May 2017 to April 2019.

Ninety percent received human immunoglobulin, and 10% received no specific treatment. None of the patients underwent plasmapheresis. The median time between the onset of symptoms and the beginning of treatment was 6 days. There was a fluctuation of symptoms (relapse) in 6% of the patients, and a new human immunoglobulin cycle was performed.

ICU admission occurred in 17% of the patients, and 15% required mechanical ventilation. The median length of ICU stay was 8 days. There was one death due to probable brainstem involvement by BE with dysautonomia1818. Styczynski AR, Malta JMAS, Krow-Lucal ER, Percio J, Nóbrega ME, Vargas A, et al. Increased rates of Guillain-Barré syndrome associated with Zika virus outbreak in the Salvador metropolitan area, Brazil. PLoS Negl Trop Dis. 2017 Aug 30;11(8)..

Figure 2 shows the cumulative probability of patient survival to the improvement outcome, defined as a 1-point reduction in the degree of disability over the observation period. Most patients showed improvement until the 10th week of observation, and the median time until the onset of improvement was 4 weeks (95% CI 1.1 to 6.2).

FIGURE 2:
Cumulative probability of improvement (Kaplan-Meier method) until the outcome of improvement in patients with GBS treated at the IHBDF from May 2017 to April 2019.

Figure 3 shows the patients were divided into two strata, 1 to 3 and 4 to 6, which had similar times for the improvement outcome, defined as a reduction of 1 point in the degree of disability, throughout the observation period regardless of the initial degree of disability (log-rank = 0.013; P = 0.908).

FIGURE 3:
Cumulative probability of improvement (Kaplan-Meier), according to the degree of disability, until the outcome of disability improvement in patients with GBS treated at the IHBDF in the period from May 2017 to April 2019.

None of the patients had positive RT-PCR results for ZIKV, DENV, or CHIKV after admission or positive serology for ZIKV and CHIKV. However, four patients had positive immunoglobulin M (IgM) serological results for dengue. Table 2 shows the characteristics of patients with GBS associated with DENV infection.

TABLE 2:
Characteristics of four patients with GBS associated with dengue virus infection treated at a tertiary referral center from May 2017 to April 2019 in Brasília, Federal District, Brazil.

DISCUSSION

The present clinical cohort described the clinical, laboratory, and electromyographic profiles of patients with GBS in Brasília, Brazil, monitored over 2 years. The current study characterized the clinical course, subtypes, and outcomes of GBS with a 1-year follow-up period. We successfully identified four patients with recent exposure to DENV infection as a potentially relevant triggering event.

Observations over 52 weeks showed that most patients showed improvement during the first 10 weeks of evolution.

The present study found that the mean age of patients with GBS was 40 years, slightly below the mean age of 51 years in other studies in South America, Asia, and the IGOS Consortium. The male-to-female ratio was 1.5:1, consistent with the literature 2525. Doets AY, Verboon C, van den Berg B, Harbo T, Cornblath DR, Willison HJ, et al; IGOS Consortium. Regional variation of Guillain-Barré syndrome. Brain. 2018 Oct 1;141(10):2866-2877.

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28. Kulkantrakorn K, Sukphulloprat P. Outcome of Guillain-Barré Syndrome in Tertiary Care Centers in Thailand. Journal of Clinical Neuromuscular Disease. 2017; 19 (2).

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-3131. Ravasio A, Pasquinelli M, Curro Dossi B, Neri W, Guidi C, Gessaroli M, et al.(Emilia-Romagna Study Group on Clinical and Epidemiological Problems in Neurology). A prospective study on the incidence and prognosis of Guillain-Barré syndrome in Emilia-Romagna region, Italy (1992-1993). Neurology 1997; 48(1):214-21.. Previous events were characterized in 83% of cases, similar to other studies2525. Doets AY, Verboon C, van den Berg B, Harbo T, Cornblath DR, Willison HJ, et al; IGOS Consortium. Regional variation of Guillain-Barré syndrome. Brain. 2018 Oct 1;141(10):2866-2877.,3232. Al-Hakem H, Sindrup SH, Andersen H, de la Cour CD, Lassen LL, van den Berg B, et al. Guillain-Barré syndrome in Denmark: a population-based study on epidemiology, diagnosis and clinical severity. Journal of Neurology. 2019; 266 (2): 440-9..

Pain frequency was consistent with that reported in a study in Denmark (55%), but much higher than in the study in Thailand3232. Al-Hakem H, Sindrup SH, Andersen H, de la Cour CD, Lassen LL, van den Berg B, et al. Guillain-Barré syndrome in Denmark: a population-based study on epidemiology, diagnosis and clinical severity. Journal of Neurology. 2019; 266 (2): 440-9.,2828. Kulkantrakorn K, Sukphulloprat P. Outcome of Guillain-Barré Syndrome in Tertiary Care Centers in Thailand. Journal of Clinical Neuromuscular Disease. 2017; 19 (2)..

Cranial nerve involvement was observed in 54% of cases, similar to the percentage reported in published reviews. However, ophthalmoparesis was present in only 7% of the patients, well below the reported value of 20%333.Donofrio PD. Guillain-Barre´ Syndrome. Continuum (Minneap Minn). 2017; 23 (5):1295-309..

Some degree of hyporeflexia/areflexia was found in 100% of the patients. The prevalence was 98% and 90% in French and Thai studies, respectively1010. Grapperon AM, Berro M, Salort-Campana E, Verschueren A, Delmont E, Attarian S. GuillainBarré syndrome subtypes: A clinical electrophysiological study of 100 patients. Revue Neurologique (Paris). 2019;175(1-2):73-80.,2828. Kulkantrakorn K, Sukphulloprat P. Outcome of Guillain-Barré Syndrome in Tertiary Care Centers in Thailand. Journal of Clinical Neuromuscular Disease. 2017; 19 (2).. A previous review found sensory deficits in 54% of the patients, higher than expected3131. Ravasio A, Pasquinelli M, Curro Dossi B, Neri W, Guidi C, Gessaroli M, et al.(Emilia-Romagna Study Group on Clinical and Epidemiological Problems in Neurology). A prospective study on the incidence and prognosis of Guillain-Barré syndrome in Emilia-Romagna region, Italy (1992-1993). Neurology 1997; 48(1):214-21. but similar to other studies (53.3%, 78%)2828. Kulkantrakorn K, Sukphulloprat P. Outcome of Guillain-Barré Syndrome in Tertiary Care Centers in Thailand. Journal of Clinical Neuromuscular Disease. 2017; 19 (2).,3232. Al-Hakem H, Sindrup SH, Andersen H, de la Cour CD, Lassen LL, van den Berg B, et al. Guillain-Barré syndrome in Denmark: a population-based study on epidemiology, diagnosis and clinical severity. Journal of Neurology. 2019; 266 (2): 440-9..

In addition, in 42% of the patients, autonomic dysfunction was higher than reported in the literature (10%, 17%)2828. Kulkantrakorn K, Sukphulloprat P. Outcome of Guillain-Barré Syndrome in Tertiary Care Centers in Thailand. Journal of Clinical Neuromuscular Disease. 2017; 19 (2).,3232. Al-Hakem H, Sindrup SH, Andersen H, de la Cour CD, Lassen LL, van den Berg B, et al. Guillain-Barré syndrome in Denmark: a population-based study on epidemiology, diagnosis and clinical severity. Journal of Neurology. 2019; 266 (2): 440-9..

The classic form was the most common (83%), and a higher value was observed compared to other studies (70% and 69%, respectively)3434. Wakerley BR, Kokubun N, Funakoshi K, et al. Clinical classification of 103 Japanese patients with Guillain-Barré syndrome. J Neurol Sciences. 2016; 43-47.,1010. Grapperon AM, Berro M, Salort-Campana E, Verschueren A, Delmont E, Attarian S. GuillainBarré syndrome subtypes: A clinical electrophysiological study of 100 patients. Revue Neurologique (Paris). 2019;175(1-2):73-80.. Only 2% of the patients had FCB and pure SMF forms. These rates vary greatly across countries. SMF frequency is 8.7% in Canada, 8% in France, 6.7% in Thailand, 17% in Japan, and 10% in Denmark1010. Grapperon AM, Berro M, Salort-Campana E, Verschueren A, Delmont E, Attarian S. GuillainBarré syndrome subtypes: A clinical electrophysiological study of 100 patients. Revue Neurologique (Paris). 2019;175(1-2):73-80.,2828. Kulkantrakorn K, Sukphulloprat P. Outcome of Guillain-Barré Syndrome in Tertiary Care Centers in Thailand. Journal of Clinical Neuromuscular Disease. 2017; 19 (2).,3232. Al-Hakem H, Sindrup SH, Andersen H, de la Cour CD, Lassen LL, van den Berg B, et al. Guillain-Barré syndrome in Denmark: a population-based study on epidemiology, diagnosis and clinical severity. Journal of Neurology. 2019; 266 (2): 440-9.,3434. Wakerley BR, Kokubun N, Funakoshi K, et al. Clinical classification of 103 Japanese patients with Guillain-Barré syndrome. J Neurol Sciences. 2016; 43-47.. The FCB form has been reported in the literature in 2%, 6.7%, and 1.9% of cases1010. Grapperon AM, Berro M, Salort-Campana E, Verschueren A, Delmont E, Attarian S. GuillainBarré syndrome subtypes: A clinical electrophysiological study of 100 patients. Revue Neurologique (Paris). 2019;175(1-2):73-80.,2828. Kulkantrakorn K, Sukphulloprat P. Outcome of Guillain-Barré Syndrome in Tertiary Care Centers in Thailand. Journal of Clinical Neuromuscular Disease. 2017; 19 (2).,3535. Martic V, Bozovic I, Berisavac I, Basta I, Peric S, Babic M et al. Three-Year Follow-Up Study in Patients with Guillain-Barré Syndrome. Canadian Journal of Neurology Sciences. 2018;45:269-74.. SGB-SMF overlap was observed in 7% of our cases, and SMF-FCB overlap was observed in 2%. There have been few reports of these forms in other studies. A previous Japanese study reported a rate lower than 1%3434. Wakerley BR, Kokubun N, Funakoshi K, et al. Clinical classification of 103 Japanese patients with Guillain-Barré syndrome. J Neurol Sciences. 2016; 43-47..

The most common form in nerve conduction studies was AIDP, consistent with the literature (58% to 66.7%)2525. Doets AY, Verboon C, van den Berg B, Harbo T, Cornblath DR, Willison HJ, et al; IGOS Consortium. Regional variation of Guillain-Barré syndrome. Brain. 2018 Oct 1;141(10):2866-2877.,2727. Cea G, Jara P, Quevedo F. Características epidemiológicas del síndrome de Guillain-Barré em población chilena: estudio hospitalario en un período de 7 años. Revista Medica de Chile 2015;143: 183-9.,2828. Kulkantrakorn K, Sukphulloprat P. Outcome of Guillain-Barré Syndrome in Tertiary Care Centers in Thailand. Journal of Clinical Neuromuscular Disease. 2017; 19 (2).,3535. Martic V, Bozovic I, Berisavac I, Basta I, Peric S, Babic M et al. Three-Year Follow-Up Study in Patients with Guillain-Barré Syndrome. Canadian Journal of Neurology Sciences. 2018;45:269-74.,3636. Méndez N, Oviedo-Pastrana M, Mattar S, Caicedo-Castro I, Arrieta G. Zika virus disease, microcephaly and Guillain-Barré syndrome in Colombia: epidemiological situation during 21 months of the Zika virus outbreak, 2015-2017. Arch Public Health. 2017 Nov 2;75:65.. The AMAN and AMSAN rates were 17% and 15%, respectively, consistent with a study in Chile that reported 26.7% axonal forms2727. Cea G, Jara P, Quevedo F. Características epidemiológicas del síndrome de Guillain-Barré em población chilena: estudio hospitalario en un período de 7 años. Revista Medica de Chile 2015;143: 183-9..

Upon admission, the most common degree of disability was Grade 4 (56%). Most cases were classical GBS and AIDP subtypes, similar to Europe and America2525. Doets AY, Verboon C, van den Berg B, Harbo T, Cornblath DR, Willison HJ, et al; IGOS Consortium. Regional variation of Guillain-Barré syndrome. Brain. 2018 Oct 1;141(10):2866-2877.. Of the demyelinating subtypes, 61% had a degree of disability greater than or equal 4. The most frequent degree of disability was 4, and 51.2% described previous infectious conditions2727. Cea G, Jara P, Quevedo F. Características epidemiológicas del síndrome de Guillain-Barré em población chilena: estudio hospitalario en un período de 7 años. Revista Medica de Chile 2015;143: 183-9..

Forty-nine percent of cases in the outcome evaluation had a degree of disability of 0 or 1, similar to the results of Thai and Canadian studies2828. Kulkantrakorn K, Sukphulloprat P. Outcome of Guillain-Barré Syndrome in Tertiary Care Centers in Thailand. Journal of Clinical Neuromuscular Disease. 2017; 19 (2).,3535. Martic V, Bozovic I, Berisavac I, Basta I, Peric S, Babic M et al. Three-Year Follow-Up Study in Patients with Guillain-Barré Syndrome. Canadian Journal of Neurology Sciences. 2018;45:269-74.. The last evaluations were performed via videoconference in some cases because of the COVID-19 pandemic.

All 37 treated patients received human immunoglobulins. Four patients did not undergo any specific treatment because they were treated in the acute phase at another hospital. The need for mechanical ventilation (15%) was well below the needs reported in a review study (30%) and GBS during the ZIKV outbreaks in Salvador, Brazil (22%) but consistent with a study in Thailand (13.3%)1717. Silva IRF, Frontera JA, Bispo de Filippis AM, Nascimento OJMD; RIO-GBS-ZIKV Research Group. Neurologic Complications Associated with the Zika Virus in Brazilian Adults. JAMA Neurology. 2017 Oct 1;74(10):1190-1198.,3131. Ravasio A, Pasquinelli M, Curro Dossi B, Neri W, Guidi C, Gessaroli M, et al.(Emilia-Romagna Study Group on Clinical and Epidemiological Problems in Neurology). A prospective study on the incidence and prognosis of Guillain-Barré syndrome in Emilia-Romagna region, Italy (1992-1993). Neurology 1997; 48(1):214-21.,3838. Lima MES, Bachur TPR, Aragão GF. Guillain-Barre syndrome and its correlation with dengue, Zika and chikungunya viruses infection based on a literature review of reported cases in Brazil. Acta Trop. 2019 Sep;197:105064.,4040. Sharp TM, Fischer M, Muñoz-Jordán JL, Paz-Bailey G, Staples JE, Gregory CJ, et al. Dengue and Zika virus diagnostic testing for patients with a clinically compatible illness and risk for infection with both viruses. MMWR Recommendations Report. 2019; 68(1):1-10..

Thirty-four patients (83%) had previous GBS events, which may be a triggering factor for immunological changes responsible for the syndrome’s pathophysiology. Twenty-nine patients (61%) had events of probable infectious etiology (upper respiratory tract infection and gastroenteritis/diarrhea), supporting the importance of infectious diseases as triggers for the process.

Gastrointestinal symptoms have been reported in the context of other ZIKV outbreaks, and these symptoms may be underrecognized clinical features of ZIKV disease1818. Styczynski AR, Malta JMAS, Krow-Lucal ER, Percio J, Nóbrega ME, Vargas A, et al. Increased rates of Guillain-Barré syndrome associated with Zika virus outbreak in the Salvador metropolitan area, Brazil. PLoS Negl Trop Dis. 2017 Aug 30;11(8)..

Symptoms and factors of exposure and history of the presentation of symptoms suggestive of infection by the three arboviruses studied were reported by 71% of the patients. However, studying the association between ZIKV, DENV, and CHIKV infections and GBS is challenging because these viruses have short viremia periods that reduce the opportunity for detection, and the available serological tests do not have adequate accuracy3939. Baud D, Gubler DJ, Schaub B, Lanteri MC, Musso D. An update on Zika virus infection. Lancet. 2017 Nov 4;390(10107):2099-2109.,4040. Sharp TM, Fischer M, Muñoz-Jordán JL, Paz-Bailey G, Staples JE, Gregory CJ, et al. Dengue and Zika virus diagnostic testing for patients with a clinically compatible illness and risk for infection with both viruses. MMWR Recommendations Report. 2019; 68(1):1-10..

However, not all patients likely described the preceding symptoms, and these patients did not provide laboratory evidence of ZIKV infection.

Four patients had positive serology results, which confirmed a recent DENV infection. There was no detectable relationship between specific laboratory tests for ZIKV and CHIKV. Perhaps the small and decreasing number of cases of ZIKV infection in Brasília, Brazil, explains this finding because we expected to observe some cases associated with this infection in Brazil and America. Brazil has the highest incidence of ZIKV infection worldwide3737. Salles TS, da Encarnação Sá-Guimarães T, de Alvarenga ESL, Guimarães-Ribeiro V, de Meneses MDF, de Castro-Salles PF, et al. History, epidemiology and diagnostics of dengue in the American and Brazilian contexts: a review. Parasit Vectors. 2018 Apr 24;11(1):264., and a higher incidence of GBS is expected in these patients4040. Sharp TM, Fischer M, Muñoz-Jordán JL, Paz-Bailey G, Staples JE, Gregory CJ, et al. Dengue and Zika virus diagnostic testing for patients with a clinically compatible illness and risk for infection with both viruses. MMWR Recommendations Report. 2019; 68(1):1-10., as reported by Stycznski1818. Styczynski AR, Malta JMAS, Krow-Lucal ER, Percio J, Nóbrega ME, Vargas A, et al. Increased rates of Guillain-Barré syndrome associated with Zika virus outbreak in the Salvador metropolitan area, Brazil. PLoS Negl Trop Dis. 2017 Aug 30;11(8). and Silva1717. Silva IRF, Frontera JA, Bispo de Filippis AM, Nascimento OJMD; RIO-GBS-ZIKV Research Group. Neurologic Complications Associated with the Zika Virus in Brazilian Adults. JAMA Neurology. 2017 Oct 1;74(10):1190-1198.. However, we did not observe a large number of cases of ZIKV infection or GBS associated with this virus in Brazil during the study period.

The incidence of infections by Zika and Chikungunya in Brasília and Brazil was 2.7 cases/100,000 inhabitants and 5.1 cases/100,000 inhabitants in 2017, 1.6 cases/100,000 inhabitants and 2.6 cases/100,000 inhabitants in 2018, and 2 cases/100,000 inhabitants and 1.2 cases/100,000 inhabitants in 2019, respectively (Official Government Epidemiological Report SVS/SES-DF).

The study's main limitation was the small sample size, which did not allow for a more detailed exploration of factors associated with prognosis. However, the cohort primarily consisted of patients with GBS treated in the public network of the Federal District over 2 years. The lack of access to patients treated in the private network is also a limitation because factors such as socioeconomic stratum may cause selection bias and affect the validity of the results. In addition, patients were not tested for Campylobacter infection, and this etiology is a triggering factor that cannot be excluded as a relevant factor for patients with recent exposure to DENV.

The data presented are useful in building local knowledge about GBS and providing a warning about the potential role of arboviruses in the pathogenesis of the disease.

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Publication Dates

  • Publication in this collection
    08 Apr 2022
  • Date of issue
    2022

History

  • Received
    10 June 2021
  • Accepted
    26 Jan 2022
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