Diagnosis and treatment of Guillain‐Barré syndrome during the Zika virus epidemic in Brazil: A national survey study

Abstract The Zika virus (ZIKV) epidemic in Brazil in 2015‐2016 was followed by an increase in the incidence of patients with Guillain‐Barré syndrome (GBS). With this national survey study, we aimed to gain a better understanding of how neurologists in Brazil are currently diagnosing and treating patients with GBS, and how this increase in incidence has impacted the management of the disease. The questionnaire consisted of 52 questions covering: personal profile of the neurologist, practice of managing GBS during and outside of the ZIKV epidemic, and limitations in managing GBS. All 3264 neurologists that were member of the Brazilian Academy of Neurology at the time of the study were invited to participate. The questionnaire was fully answered by 171 (5%) neurologists. Sixty‐one percent of neurologists noticed an increase in patients with GBS during the ZIKV epidemic, and 30% experienced an increase in problems in managing GBS during this time. The most important limitations in the diagnosis and management of GBS included the availability of nerve conduction studies (NCS), beds in the Intensive Care Unit (ICU) and referral to rehabilitation centers. Most neurologists did not use a protocol for treating patients with GBS and the treatment practice varied. Increasing availability of NCS and beds in the ICU and rehabilitation centers, and the implementation of (inter)national guidelines, are critical in supporting Brazilian neurologist in their management of GBS, and are especially important in preparing for future outbreaks.


| INTRODUCTION
Guillain-Barré syndrome (GBS) is the most common acute paralytic neuropathy worldwide, with a global incidence of~1-2 per 100 000 person-years. 1 GBS typically presents as progressive weakness and sensory signs, starting in the distal legs and progressing to the arms and facial muscles. 2 Disease progression is rapid and often severe, with~20% of patients requiring mechanical ventilation due to involvement of respiratory muscles. 2 Treatment for GBS generally consists of multidisciplinary supportive medical care and immunotherapy. Both intravenously administered immunoglobulin (IVIg) and plasma exchange are proven effective therapies for GBS. 3 GBS is an immune-mediated neuropathy and in most cases presumed to be triggered by specific types of infections. 2 Several pathogens have been associated with GBS in case-control studies. 4 Most recently, infection with Zika virus (ZIKV) was associated with GBS, when incidence peaked during the outbreaks of ZIKV in Latin America in 2015-2016. 5,6 Brazil was one of the countries most severely affected by the ZIKV epidemic, with~370 000 cumulative ZIKV cases (suspected or confirmed) reported by the World Health Organization and Ministry of Health between December 2015 and January 2018. 7 The actual incidence is likely to be even higher, as cases may have gone underreported, considering ZIKV usually causes a mild and uncomplicated or subclinical infection. The number of reported cases and the incidence in Brazil was highest in the Northeast, Southeast, and Center-West regions ( Figure 1). 8 It is unknown how neurologists in Brazil are currently managing GBS and if the ZIKV epidemic has affected the diagnosis and treatment of GBS patients. Apart from a protocol mainly directed to guide clinicians in decisions on therapy, there are currently no detailed national Brazilian guidelines for the diagnosis and management of GBS, and at the time of the survey no international guidelines were available. 9

| Study population
All the neurologists that were member of the Brazilian Academy of Neurology (Academia Brasileira de Neurologia) were approached through the Academy to participate in the survey study. They were contacted via e-mail, containing a link to the online Limesurvey platform. The first invitation was sent in February 2019 and participants had a total of 70 days to answer the questionnaire. Five reminders were sent during that time. Discrepancies in interpretation were discussed to reach consensus.

| RESULTS
A total of 3264 neurologists were member of the Brazilian Academy of Neurology at the start of the survey and were invited to participate in the study. Of this group, 254 (8%) answered the questionnaire, and of these responses, 171 (5%) were complete. For the analysis, only fully completed questionnaires were used.

| Profile of the neurologists
The profile of the responding neurologists is described in Table 1. The responders are well-varied regarding age, field of interest, and employment in the private vs public sector. The majority of neurologists work in one hospital (49%), some in two (36%) and a few in three (15%).

| Diagnosis
The clinical practice in diagnosis and treatment of GBS is shown in  Nerve conduction studies (NCS) were available at the hospital of 57% of neurologists. Fifteen percent of the neurologists that indicated NCS were not available at their hospital did not or could not always refer the patient to a dedicated clinic. NCS were frequently or (almost) always indicated in the diagnosis of GBS according to 77% of neurologists, but fewer neurologists (66%) frequently or (almost) always made use of this diagnostic tool (Figure 3). This may be explained by limitations in NCS, that were frequently or (almost) always present in 36% of the responders, and included limited availability of personnel (65%), equipment (57%), high costs of the procedure (24%), and transportation issues

| Treatment and care
Most of the neurologists did not use a specific protocol to treat GBS When asked what they consider to be the best treatment for GBS Although the preferred treatment was (almost) always available for most responders, for 11% treatment was available only sometimes, infrequently, very rarely or even never (Figure 4). When the preferred treatment was not available, alternative treatment most often consisted of plasmapheresis or IV corticosteroids. Reasons for limited availability of the preferred treatment included high costs (55%), limited access to IVIg within the public health system (33%) and staff or logistics-related issues (38%).
If a patient does not respond to treatment, 51% of neurologists would switch to another treatment (eg, plasmapheresis if first treatment was IVIg or vice-versa), 27% would repeat the same treatment, and for 12% both repeating and switching therapy were an option. Of the responders that would repeat treatment, 48% would repeat for a maximum of two times, and 12% had no restrictions in how often they would repeat treatment. Neurologists who indicated to have expertise in neuro-immunology or neuromuscular diseases were more likely to repeat treatment (P = .02), and less likely to switch treatment (P < .001) compared to other neurologists. Treatment practice did not significantly differ between neurologists who had more experience (>5 years) or who saw more (≥5) GBS patients yearly.
Although an ICU was available in the hospital of 96% of neurologists, 55% experienced limitations in transferring GBS patients to the ICU (Figure 4). A limited amount of beds at the ICU was the main problem, indicated by 98% of the responders.  Protocolo Clínico e Diretrizes Terapêuticas (n = 5), American Academy of Neurology Guideline on immunotherapy for GBS (n = 1), BMJ Best Practice guideline for GBS (n = 1). b Multiple answers were possible. Answer option "Inability to walk for any distance" was considered mutually exclusive for "Inability to walk for 10m.". c Only neurologists that indicated that the preferred treatment was not always available were asked this question. d PE or corticosteroids (n = 3), PE or IVIg (n = 1), referral to other hospital (n = 1), non-pharmaceutical support (n = 2). e Start (intensive) rehabilitation (n = 2), depends on the individual patient (n = 2), re-evaluation of diagnosis (n = 3). Limitations in the diagnosis or treatment of GBS were experienced frequently. Any limitations in NCS were experienced by 60%, in F I G U R E 4 Management: frequency and availability of treatment, ICU and rehabilitation. This figure shows how often neurologists encountered limitations in the availability of the best treatment for GBS, ICU admission, and referral to a rehabilitation unit ("no limitations"), and how often patients received in-hospital rehabilitation and were referred to a rehabilitation unit ("frequency"). For the variable "frequency referral to rehabilitation center," one responder used the answer option "other" F I G U R E 3 Diagnosis: indication, frequency, and availability of CSF and NCS. This figure displays how often neurologists considered CSF or NCS to be indicated in the diagnosis of GBS ("indication"), how often they used these diagnostics tools ("frequency"), and how often they encountered limitations in using these diagnostics ("no limitations") ICU care by 55%, and in referring patients to a rehabilitation center bỹ 30% of neurologists. Especially the lack of availability of sufficient intensive care for GBS patients is worrying, as this may directly affect morbidity and even mortality of these patients. Limitations were generally more frequently experienced by neurologists working in the Northeast and Center-West of Brazil, which corresponds to a lower socioeconomic status in these regions, as reflected by regional contribution to the gross domestic product. 14 Both neurologists working at the public and private sector experienced these limitations, but they were more frequent in the public health system. So although the pub- tion, although effectivity of plasmapheresis and IVIg has not been sufficiently studied in patients still able to walk. 18,19 This treatment practice is also common outside of Brazil, and can likely be explained by the lack of evidence and the absence of international guidelines for treatment in these situations. 13 This study has several limitations. First, the percentage of responding neurologists was limited, and may be biased toward specific neurologists, for instance those working in the neuromuscular field, in academic hospitals, or in certain regions. Second, the results presented reflect the estimates and opinions of neurologists, that may deviate from the actual practice.