key: cord-0835619-sojj1dyi authors: Papri, Nowshin; Islam, Zhahirul; Leonhard, Sonja E.; Mohammad, Quazi D.; Endtz, Hubert P.; Jacobs, Bart C. title: Guillain–Barré syndrome in low-income and middle-income countries: challenges and prospects date: 2021-03-01 journal: Nat Rev Neurol DOI: 10.1038/s41582-021-00467-y sha: 9a4a91040c5ad71a99aaeb032d715a5d0e362cb0 doc_id: 835619 cord_uid: sojj1dyi The epidemiology, clinical characteristics, management and outcome of Guillain–Barré syndrome (GBS) differ between low-income and middle-income countries (LMIC) and high-income countries (HIC). At present, limited data are available on GBS in LMIC and the true incidence of GBS in many LMIC remains unknown. Increased understanding of GBS in LMIC is needed because poor hygiene and high exposure to infections render populations in LMIC vulnerable to GBS outbreaks. Furthermore, insufficient diagnostic and health-care facilities in LMIC contribute to delayed diagnosis in patients with severe presentations of GBS. In addition, the lack of national clinical guidelines and absence of affordable, effective treatments contribute to worse outcomes and higher mortality in LMIC than HIC. Systematic population-based surveillance studies, cohort and case–control studies are required to understand the incidence and risk factors for GBS. Novel, targeted and cost-effective treatment strategies need to be developed in the context of health system challenges in LMIC. To ensure integrative rehabilitation services in LMIC, existing prognostic models must be validated, and responsive outcome measures that are cross-culturally applicable must be developed. Therefore, fundamental and applied research to improve the clinical management of GBS in LMIC should become a critical focus of future research programmes. Guillain-Barré syndrome (GBS) is an immune-mediated polyradiculoneuropathy with an acute onset that affects 100,000 people worldwide annually [1] [2] [3] . GBS is characterized by rapidly progressive ascending weakness that initially affects the limbs and can eventually affect the cranial and respiratory muscles. Several infectious agents have been identified as triggers for the development of GBS, and clusters of this disease can be associated with outbreaks such as the Zika virus epidemic [4] [5] [6] . The severity of GBS is highly variable, ranging from mild distal limb weakness to complete paralysis, respiratory failure and even death. Several variants of GBS have been defined on the basis of their clinical presentation, including a pure motor variant, paraparetic variants and Miller Fisher syndrome (MFS) 7, 8 , which is characterized by the clinical triad of ophthalmoplegia, ataxia and areflexia 7 . Several subtypes of GBS have also been identified on the basis of electrophysiological features 1-3 , including acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN) 2, 9, 10 . Patients with AIDP usually have the classic sensorimotor variant of GBS, whereas those with AMAN typically have the pure motor variant 8 . In some patients with axonal GBS, both sensory and motor fibres are affected; this variant is termed acute motor and sensory axonal neuropathy (AMSAN) and is sometimes considered to be a severe variant of AMAN 2 . Plasma exchange and intravenous immunoglobulin infusions are equally effective therapies for all variants of GBS [2] [3] [4] 11 . Considerable variation between countries and/or regions is evident in the epidemiology, subtypes and management of GBS 12 . These differences are thought to be related to environmental and economic factors as well as to health awareness and behaviour. Poor hygiene and sanitation, unsafe drinking water and frequent exposure to pathogens render the populations in low-income and middle-income countries (LMIC)defined in July 2019 by the World Bank as countries having an annual gross national income per capita of 2) compared with 40-60% of patients from Europe and North America, where the AIDP subtype is most prevalent 12, 52 . Overall, GBS is considered to be the consequence of a preceding infection that triggers an immune response that is responsible for the demyelination and axonal degeneration of peripheral nerves and nerve roots. Treatment with immunomodulatory agents, such as vaccines or biologic drugs, have also been associated with GBS in rare individuals. Other events, including surgery and malignancy, have been temporally related to GBS; the underlying mechanism of GBS in such individuals is not clear [53] [54] [55] . Approximately two thirds of patients with GBS report symptoms of an infectious disease within the 4 weeks preceding the onset of weakness 2 . Upper respiratory tract infection is the most common antecedent event and is reported by 22-53% of all patients with GBS in Europe, North America, South America and parts of Asia (Taiwan, Nepal, Pakistan, Japan and Malaysia) 10, 12, 37, 47, 56 . The frequency of antecedent respiratory tract infections is even higher in paediatric patients with GBS (50-70%) 25 . By contrast, in India and Bangladesh, gastroenteritis is the most frequent antecedent event associated with GBS (36-47%) 12, 57 . Worldwide, the most frequently identified infectious agent that triggers GBS is C. jejuni, which is an important bacterial cause of gastroenteritis and food poisoning 30, 58 . The reported frequencies of antecedent C. jejuni infection in patients with GBS differ between studies as well as between countries and regions; for instance, C. jejuni infection is substantially more frequent among patients with GBS from Curaçao, China and Bangladesh (~60-70%) than in those from all other countries (30-32%) 14, 28, 32, 48 . The increased frequency of C. jejuni infection in these regions could be explained by their hygienic infrastructure and environmental or host-related factors, including diet 14, 27, 44, 59 . C. jejuni is an established cause of MFS that is probably more frequent in LMIC 60 be responsible for triggering MFS in countries where C. jejuni is less common. The reported frequencies of antecedent infections in a given population can change over time. For example, China has undergone rapid socioeconomic development and improvements in health services over the past 50 years. A recent study of GBS in China found a lower incidence of antecedent C. jejuni infection (27% in data from 2013-2017) 59 than had previously been reported (66% in data from 1991-1992) 32 . In addition, the trend towards increased life expectancy in China over a similar time period could have decreased the incidence of C. jejuni infections, which are more common in younger individuals. We are not aware of any public health interventions undertaken during this time by the Chinese government aimed specifically at reducing the number of C. jejuni infections 59, 61 . However, public health interventions can both reduce the prevalence of Campylobacter infections and decrease the incidence of GBS: in response to high rates of C. jejuni infection between 1980 and 2006, the New Zealand government introduced a national intervention to reduce contamination with Campylobacter spp. in poultry. Within 2 years, the country achieved a 52% decline in campylobacteriosis and a simultaneous 13% reduction in GBS hospital admissions 62 . Whether such infection control interventions are feasible in other countries and regions (such as LMIC) remains to be fully explored. Other infectious agents that have been detected at higher frequencies in patients with GBS than in the background population are cytomegalovirus (10-13%), Epstein-Barr virus (10%), M. pneumoniae (5%; predominantly [75] [76] [77] . However, an epidemiological study in the UK found no increase in the incidence of GBS during the COVID-19 pandemic 78 . Further studies are required to confirm the potential relationship between SARS-CoV-2 infection and GBS. Immunopathogenesis. The geographic differences in clinical and electrophysiological phenotypes of GBS in LMIC and HIC might be in part caused by differences in the rates of preceding infections that tend to trigger different types of GBS. For example, C. jejuni infections lead to the development of predominantly (but not exclusively) the axonal type of GBS 30 . In C. jejuni-related GBS, an immune response is triggered owing to molecular mimicry between C. jejuni lipo-oligosaccharides and human nerve gangliosides, which results in the production of cross-reactive antibodies that activate complement and damage nerves 2 . The pathophysiological mechanisms leading to GBS after infections other than C. jejuni have not yet been clearly defined, but similar mechanisms might also play a part in other bacterial infections related to GBS, such as M. pneumoniae and H. influenzae, although these have been less extensively investigated. The demyelinating and sensorimotor forms of GBS are usually preceded by infection with viruses, such as cytomegalovirus or Epstein-Barr virus; however, the immunopathogenesis remains to be elucidated 10 . Similarly, the specific components of the Zika virus that trigger the immune response leading to GBS have not yet been clarified 79 . Of the patients with SARS-CoV-2associated GBS, 77-80% had the demyelinating electrophysiological subtype and ~70% had classic sensorimotor GBS 80, 81 . Whether this is the typical phenotype of SARS-CoV-2-related GBS is presently unclear owing to the limited number of reported cases. Despite the strong associations between specific infectious agents and GBS, the overall risk of developing GBS after infection is very small; for example, only one in 1,000-5,000 patients with C. jejuni infection will develop GBS in the subsequent 2 months. One factor that determines this low risk is the requirement for carbohydrate mimicry (which is not present in all C. jejuni strains) to develop the cross-reactive antibody response to gangliosides that evolves into GBS 2,3,10 . However, genetic and nutritional factors might also influence the patient's susceptibility to producing such antibodies [82] [83] [84] . Poor nutritional status, and specifically malnutrition, alters the dysfunctional immune responses implicated in the pathogenesis of various autoimmune diseases 85 . Immune response activation following an infection has also been associated with genetic polymorphisms. Several studies have found associations between GBS and polymorphisms in the TNF gene (which encodes tumour necrosis factor) and the MBL2 gene (which encodes mannose-binding protein C) 2,82-84 . Although GBS usually occurs sporadically, several outbreaks of this disease have been linked to epidemics of infectious diseases that can trigger GBS. Surges in GBS cases in China (2007) However, only ~2 in 10,000 patients infected with Zika virus went on to develop GBS, suggesting that a relatively large outbreak of Zika virus is necessary to increase the incidence of GBS 88 . The origins of emerging infectious diseases correlate positively with specific socioeconomic, environmental and ecological factors, which provide a basis for identifying regions where new infections are most likely to originate (so-called emerging disease hotspots) 89 . Zoonoses from wildlife represent the most important and growing threat of emerging infections to global health, whereas vector-borne diseases are responsible for about 25% of emerging infectious diseases. Hotspots for emerging infectious diseases are more common at lower latitudes where wild animals and arthropod vectors reside, such as sub-Saharan Africa and parts of Asia, which mainly consist of LMIC 89 . Other vector-borne viruses transmitted by the same Aedes family of mosquitoes as Zika virus (such as chikungunya and dengue) have also been associated with surges in GBS cases 90, 91 . Therefore, these regions are particularly at risk of new outbreaks of GBS. In response to the Zika virus outbreak, several projects have been set up in Latin America to prevent transmission of vector-borne diseases, including surveillance systems for arboviruses and vector control programmes 92 . Further investment in these projects and their implementation in at-risk areas beyond Latin America could help to reduce the likelihood of future outbreaks of GBS. International disease surveillance initiatives could also help identify new outbreaks of GBS. The ongoing acute flaccid paralysis (AFP) surveillance programmeoriginally devised for the surveillance of poliomyelitis -is a useful early warning signal that flags changes in the prevalence of AFP in children up to 15 years of age. Studies conducted in China and Bangladesh show that GBS is now the predominant cause of AFP among www.nature.com/nrneurol 0123456789();: children in this age group, suggesting that AFP surveillance programmes could be expanded to detect changes in the incidence of GBS. Data from this programme have already been used to calculate crude incidence rates of GBS among children 26, 93 . Extending the AFP surveillance programme to other age groups, and GBS case ascertainment using the Brighton Collaboration criteria to assess the degree of diagnostic certainty, might help to monitor the incidence of GBS 94 . Diagnosis of GBS is mainly based on clinical features, supported by cerebrospinal fluid examination and nerve conduction studies. The National Institute of Neurological Disorders and Stroke (NINDS) criteria and the Brighton Collaboration criteria are the most commonly used sets of validated diagnostic criteria for GBS [1] [2] [3] 19, [95] [96] [97] [98] [99] . Patients with GBS can present with remarkably diverse clinical features. In patients with typical GBS, the key presenting feature is ascending bilateral symmetrical weakness that progresses over a period of 12 h to 28 days before a plateau is reached [1] [2] [3] 9, 10 . Most patients develop generalized hyporeflexia or areflexia, although tendon reflexes can be normal or even exaggerated in the initial stages. More than half of patients with GBS develop cranial nerve deficits, including bilateral facial weakness, bulbar weakness or extraocular motor dysfunction. In addition to muscle weakness, patients can also experience sensory disturbances, ataxia, muscle pain or radicular pain and signs of autonomic dysfunction, including blood pressure fluctuations and cardiac arrhythmia [1] [2] [3] 12 . This diversity can complicate diagnosis in the early stages of GBS, especially in patients with atypical findings -for instance, the ~10% of patients who have normal or brisk deep tendon reflexes and the ~8% of patients who present with only paraparesis 100 . Children with GBS might also present with atypical features such as pain, refusal to walk or an abnormal gait; indeed, GBS is correctly diagnosed at admission in only one-third of affected preschool-aged children 2 . Diagnosis is generally even more challenging in LMIC, where facilities for cerebrospinal fluid examination and nerve conduction studies might not be readily available, which leads to multiple referrals of patients and diagnostic delay. In one prospective multinational cohort study, the median interval between the onset of weakness and study entry was 5 days in the Netherlands compared with 10 days in Bangladesh 96 . Studies conducted in Africa have also found lengthy intervals of up to 19 days between the onset of weakness and hospitalization 38 . This delay could lead to under-reporting of GBS in LMIC, as some patients with severe disease might die before reaching the hospital. Moreover, patients with mild symptoms might not seek treatment or recover before reaching a hospital. The relationships between C. jejuni infection and antibodies against the GM1, GM1b, GD1a, GalNAc-GD1a and GQ1b gangliosides in patients with GBS are well established 2 . Some studies have suggested an association between the presence of anti-GM2 antibodies and a recent cytomegalovirus or Epstein-Barr virus infection 59, 101 . However, serological tests to detect antiganglioside antibodies are not routinely performed at diagnosis, as negative test findings cannot rule out GBS 2 . Furthermore, most of these serological tests require sophisticated techniques and trained personnel that might not be available in LMICs. In addition, an extensive list of differential diagnoses might need to be excluded. The differential diagnosis of GBS depends on the clinical presentation and variant of GBS (box 1) and is also likely to differ between countries and regions, owing to local variations in the prevalence of infectious diseases, nutritional deficiencies or intoxications, autoimmune diseases and malignancies. As no region-specific information on the differential diagnosis of GBS was included in published studies, we conducted a small survey (Supplementary Information) to obtain insight into this important characteristic. The survey was sent to GBS experts working in LMIC within our network, who were asked in turn to distribute the questionnaire to other neurologists in their networks. In total, 17 neurologists (of whom seven frequently see paediatric patients) and two paediatric neurologists working in LMIC returned the questionnaire. Their responses revealed that the differential diagnosis of GBS is generally comparable between LMIC and HIC, although some important differences were noted (N.P., S.E.L., Q.D.M. and B.C.J., unpublished observations). For example, sarcoidosis, Sjögren syndrome, Lambert-Eaton myasthenic syndrome and mitochondrial disease seem to be less frequent diagnoses among patients suspected of GBS in LMIC than in HIC. Other diagnoses, such as hypokalaemic thyrotoxic periodic paralysis, organophosphate intoxication, botulism, rabies, polio and tetanus, seem to be more frequent in LMIC than in HIC. Furthermore, the infectious causes of transverse myelitis, acute flaccid myelitis and polyradiculoneuritis differ between LMIC and HIC. Lyme borreliosis and enterovirus D68 or A71 infection are rarely seen outside Europe and North America, whereas infections with HIV, HTLV-1 and arthropod-borne viruses -including Zika virus, chikungunya virus and West Nile virusare frequently reported in several LMIC. These differences might reflect geographic variation in the spread of arthropod vectors (such as those carrying arboviruses) or in the incidence of infectious diseases. For example, polio and rabies eradication programmes have been more successful in HIC than in LMIC. Other explanations might include resource limitations in LMIC that preclude the diagnosis of complex systemic disorders such as Sjögren syndrome and differences in the ages of the populations at risk. The differential diagnosis of paediatric GBS differs from that in adults owing to the presence of atypical or non-specific features that complicate the diagnosis, such as meningism or poorly localized pain 102, 103 . Furthermore, vascular causes, vitamin deficiencies, drug-induced myopathy or polyneuropathy and chronic inflammatory demyelinating polyneuropathy occur less frequently in children than in adults 102, 103 . These differences between adults and children in the differential diagnosis of GBS occur in both HIC and LMIC, although (as reported for adults) the infectious causes Nature reviews | Neurology of conditions that mimic paediatric GBS differ between LMIC and HIC. Management of GBS requires a multidisciplinary approach including supportive medical care and immunotherapy. Intravenous immunoglobulin (0.4 g/kg for 5 days) and plasma exchange (usually five sessions at 200-250 ml/kg) are proven and equally effective treatments for GBS 3, 11, 104 . However, most randomized controlled trials that evaluated the effectiveness of these two treatments for GBS were conducted in populations from HIC. These trials mainly included adult patients who were treated either with intravenous immunoglobulin within 2 weeks or with plasma exchange within 4 weeks after the onset of weakness 11, 104 . Included patients had a GBS disability score of ≥3 and the majority had the AIDP subtype of GBS 11, 104 . Therefore, the efficacy of these therapies might differ in LMIC, where AMAN and AMSAN are prevalent and patients usually present to hospital in the later stages of disease than they do in HIC. Considerable variations in treatment protocols for GBS are observed throughout the world 21 . In general, intravenous immunoglobulin is considered the first choice of treatment as it is easy to administer, widely available and associated with a reduced frequency of adverse effects compared with plasma exchange 11, 105 . Conversely, plasma exchange is less costly than intravenous immunoglobulin and could theoretically be a preferred treatment option for GBS in LMIC [106] [107] [108] . However, in practice, clinicians in LMIC face various limitations and obstacles that were not considered in existing GBS therapeutic studies. For example, owing to the low per capita income and lack of coverage by the national health insurance system in Bangladesh, neither intravenous immunoglobulin (~US$12,000-16,000) nor plasma exchange (~US$4,500-5,000) are affordable for the majority of patients 18 . Therefore, only 10-12% of patients in Bangladesh receive one of these treatments, even though most patients with GBS in Bangladesh are severely affected. For instance, 93% of patients from Bangladesh were unable to walk independently at nadir (GBS disability score >2) in comparison with 76% of patients in Europe, America or other parts of Asia 12, 18, 22, 109 . This situation underscores the need for low-cost and effective treatment strategies for GBS in LMIC. Small volume plasma exchange (SVPE) is a novel, relatively low cost (~$500), simple technique for selective removal of plasma, and has been shown to be a safe and feasible treatment for GBS in resource-limited settings such as India and Bangladesh 18, 110 . However, as the efficacy of SVPE has only been shown in a small number of patients, large-scale studies are required before this technique can be implemented in routine clinical practice. Complement inhibitors are a new focus in the treatment of GBS in HIC. Eculizumab, a humanized monoclonal recombinant antibody against complement factor 5, is currently being studied in the UK and Japan 71, 105 . Another humanized antibody against complement factor 3 was shown to be safe and well tolerated in patients with GBS, Guillain-Barré syndrome. a Polio has been eradicated in most regions, with the exception of several countries in sub-Saharan Africa and Southeast Asia (mostly Pakistan), where sporadic cases can occur. Although this box mainly focuses on the differential diagnosis of GBS in adults, b diagnoses that are more common in children than in adults, and c diagnoses that are less common in children than in adults are indicated. www.nature.com/nrneurol GBS 111 , and efficacy trials of this agent are currently ongoing in Europe, the USA and Asia. Although the high cost of these biologic agents is likely to greatly restrict their use in patients with GBS from LMIC, such drugs might be made available for specific indications within LMIC at affordable price levels in the future; for instance, HIV drugs have been made available to some African countries at much lower prices than in HIC 112 . Moreover, several different phases of efficacy trials for complement factor 3 inhibitors are currently ongoing in patients in Bangladesh, which indicates that research groups in some LMICs are able to conduct treatment trials in accordance with the latest scientific methods and regulatory requirements. We hope that this experience will lead to opportunities to develop affordable treatments for patients with GBS in LMIC in future. Admission to the ICU is recommended for patients with GBS who have imminent respiratory insufficiency, severe autonomic dysfunction with cardiovascular instability, severe swallowing dysfunction and/or diminished cough reflex or rapidly progressive weakness 109, [113] [114] [115] [116] . However, in LMIC the number of ICU beds is limited and ICU services in private hospitals are too costly (~US$300-1,200 daily) for most patients 71, 117 . A study from Bangladesh found that the absence of ICU support when required was the strongest risk factor for death in patients with GBS 22 . In most studies worldwide, the mortality rate for GBS is 2-10% 9,10,97 although disparities are evident between regions. For example, reported mortality rates are 2-7% in Europe and North America 10, 12, 19, 118 , 13% in Hong Kong 42 , 14-17% in Bangladesh 12, 14, 22 and 16% in Egypt 119 . Moreover, access to integrative rehabilitation services is limited in LMIC, which can adversely affect recovery and long-term quality of life of patients with GBS 120 . Across the globe, ~20% of patients with GBS are unable to walk unaided 6 months after disease onset 2,3,9,10,97,121 and this rate is higher (30-40%) in countries such as Bangladesh where AMAN predominates and most patients do not receive immunotherapy 12, 14, 122 . In addition to physical complications, a substantial proportion of patients in HIC experience residual problems, including persistent pain (~35-40%), fatigue (60-80%) and anxiety or depression (6-7%) 2, 123, 124 . No data have been reported on rates of these complications in LMIC. However, as most patients with GBS in LMIC only receive supportive care, these sequelae are also likely to vary between countries and to be worse in patients in LMIC than in those in HIC. The ability to predict which patients with GBS will develop respiratory insufficiency or have a poor prognosis has been a long-held desire worldwide, as it would enable physicians to take the necessary precautions and provide additional treatment for the patients most at risk 47, 125 . To this end, the Erasmus GBS Respiratory Insufficiency Score (EGRIS) was developed to predict the risk of requiring mechanical ventilation within 1 week and the Erasmus GBS Outcome Score (EGOS) and modified EGOS (mEGOS) were developed to predict the outcomes in patients with GBS at 6 months 47,116,125 . However, these tools were derived and validated in cohorts from European countries and might not be applicable worldwide. Indeed, a study from northeast Brazil found that EGOS was not a good predictive tool in that population 126 . By contrast, both EGRIS and mEGOS can accurately predict GBS outcome in populations from Japan and Malaysia 127, 128 . Therefore, these models might need to be validated or adapted before they can be used in LMIC. Various measures have been employed to capture outcomes in clinical trials of GBS around the world. Improvement in GBS disability scale scores is the main prognostic variable in the majority of studies. The Rasch-built Overall Disability Score (RODS), Overall Neuropathy Limitations Scale (ONLS), and Fatigue Severity Scale (FSS) were developed as outcome measures for clinical trials and are used to assess disability, activity limitations and fatigue, respectively, in patients with GBS [129] [130] [131] . However, these tools were developed in cohorts of patients with GBS from HIC and the questions might not be culturally appropriate in LMIC. At present, only limited data are available on GBS in LMIC. Most studies in LMIC were conducted in South Asia (Bangladesh and India) and publications from other LMIC are scarce, especially from Africa. LMIC are hotspots for many emerging infectious disease outbreaks, some of which have been associated with GBS. Therefore, publications from LMIC are often related to outbreaks of GBS associated with specific antecedent infectious diseases. Owing to the lack of well-designed epidemiological studies, the true incidence of GBS in many LMIC remains largely unknown. The long intervals between onset of weakness and hospitalization that are frequently observed in patients in LMIC might introduce selection bias at the hospital level, as patients with mild symptoms might not reach the health system and severely affected individuals might die before reaching the hospital. Moreover, diagnostic facilities, health-care infrastructure and adequately trained health professionals are frequently lacking in LMIC. The absence of national treatment guidelines and high costs of existing treatments relative to local wages contribute to the worse outcomes and higher mortality rates of GBS in LMIC compared with HIC. Finally, current models for predicting the outcome of GBS might not be valid in LMIC, owing to variations in disease severity, clinical presentation, electrophysiological subtypes and management. A number of strategies can address these challenges. Firstly, the expansion and improvement of GBS research capacity in LMIC is required. Systematic population-based surveillance and cohort studies that employ accurate standardized case definitions are needed to understand and monitor the incidence and overall burden of GBS. Case-control studies are crucial to identify the risk factors associated with GBS and to detect new antecedent infections that trigger GBS in LMIC. Observational cohort studies are important to define the clinical course of GBS and the factors that influence and predict this course. An example of a cohort study of GBS that is ongoing globally in both Nature reviews | Neurology LMIC and HIC is the International GBS Outcome Study (IGOS) 96 . The standardized trial protocol and web-based data entry system used in this international prospective cohort study are an example of how methodological differences between GBS studies conducted in different regions and countries might be overcome. However, African and Latin American countries and regions are under-represented in IGOS, and expanding the study to these regions and the long-term sustainability of this global initiative needs to be assured. Nonetheless, IGOS has already highlighted differences in the presentation and outcome of patients with GBS between HIC and LMIC such as Bangladesh, which provide insight into the challenges associated with caring for these patients in LMIC that might facilitate future research 12 . Affordable and cost-effective treatment strategies need to be developed and multinational efficacy trials are required to study and scale-up innovative treatment approaches. Several randomized controlled trials, including a safety, feasibility and efficacy trial of SVPE and a phase I (leading to phase II-III) trial of a new investigational drug are currently being conducted in Asia, Europe and the USA. Additional clinical intervention studies of innovative and affordable treatments need to be designed, taking into account the specific context of the health system challenges in LMIC. A sustainable clinical trial infrastructure including physical health-care facilities and adequately trained health professionals needs to be established to support research into GBS in LMIC; these efforts should include high-quality diagnostic laboratories and training programmes for health-care professionals involved in the management of patients with GBS and in clinical research. Moreover, existing prognostic models need to be validated and adapted for use in LMIC. Such tools would help clinicians in LMIC to accurately identify the patients most in need of ICU care at an early stage, thereby improving the management of individual patients and increasing the efficiency of ICU services in low-resource settings. Valid, responsive and cross-culturally applicable outcome measures need to be developed to improve our understanding of the long-term outcome of GBS in LMIC and to optimize the management of patients in rehabilitation services. Patients and their caregivers can also contact the GBS|CIDP Foundation International for support. In conclusion, GBS is an under-reported disease in LMIC, although the limited available evidence suggests that the disease has a more severe clinical course in LMIC and that affected patients in LMIC have worse outcomes than do their counterparts in HIC. This Review highlights the most important knowledge gaps and provides suggestions and recommendations for future research. Increasing the breadth and quality of fundamental and applied research should become a critical focus to improve the clinical management of GBS in LMIC in the future. More than 100 years after the first description of the syndrome by George Guillain, Jean Alexandre Barré and André Strohl, now is the time to reduce the disease burden of GBS in LMIC. Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria Guillain-Barré syndrome: pathogenesis, diagnosis, treatment and prognosis Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome Guillain-Barré syndrome associated with Zika virus infection in Colombia Diagnosis and treatment of Guillain-Barré syndrome during the Zika virus epidemic in Brazil: a national survey study Guillain-Barré syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study Guillain-Barré syndrome and variants Serial electrophysiological findings in Guillain-Barré syndrome not fulfilling AIDP or AMAN criteria Guillain-Barré syndrome Guillain-Barré syndrome Immunotherapy for Guillain-Barré syndrome: a systematic review Regional variation of Guillain-Barré syndrome Data: World Bank Country and Lending Groups Axonal variant of Guillain-Barré syndrome associated with Campylobacter infection in Bangladesh Public health hazards due to unsafe drinking water Association study between an outbreak of Guillain-Barré syndrome in Jilin, China, and preceding Campylobacter jejuni infection Binational outbreak of Guillain-Barré syndrome associated with Campylobacter jejuni infection, Mexico and USA Small volume plasma exchange for Guillain-Barré syndrome in resource-limited settings: a phase II safety and feasibility study Diagnosis of Guillain-Barré syndrome in children and validation of the Brighton criteria Diagnostic and classification criteria for the Guillain-Barré syndrome Current treatment practice of Guillain-Barré syndrome High mortality from Guillain-Barré syndrome in Bangladesh Guillain-Barré syndrome in the elderly: experience from a tertiary-care hospital in India Population incidence of Guillain-Barré syndrome: a systematic review and meta-analysis The epidemiology of Guillain-Barré syndrome worldwide High incidence of Guillain-Barré syndrome in children Guillain-Barré syndrome Gastroenteritis-associated Guillain-Barré syndrome on the Caribbean island Curacao Seasonal variation in Guillain-Barré syndrome: a systematic review, meta-analysis and Oxfordshire cohort study Infectious and noninfectious triggers in Guillain-Barré syndrome Guillain-Barré syndrome, influenza, and influenza vaccination: the epidemiologic evidence Guillain-Barré syndrome in northern China: relationship to Campylobacter jejuni infection and antiglycolipid antibodies Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED) Seasonal variation of enteropathogens in infants and preschoolers with acute diarrhea in western Mexico Guillain-Barré syndrome in Kenya: a clinical review of 54 patients Intravenous immunoglobulin vs. plasma exchange in treatment of mechanically ventilated adults with Guillain-Barré syndrome Guillain-Barré syndrome in southern Taiwan: clinical features, prognostic factors and therapeutic outcomes Guillain-Barré syndrome in northern Tanzania: a comparison of epidemiological and clinical findings with western Norway Epidemiology and prognostic factors of inpatient mortality of Guillain-Barré syndrome: a nationwide population study over 14 years in Asian country Guillain-Barré syndrome in Ethiopian patients Mortality in mechanically ventilated patients of Guillain-Barré syndrome Outcomes of patients with Guillain-Barré syndrome -experience from a tertiary care hospital of a developing Asian country and review of regional literature Campylobacter infection as a trigger for Guillain-Barré syndrome in Egypt Clinical characteristics of Guillain-Barré syndrome in a tropical country: a Brazilian experience Treatment guidelines for Guillain-Barré syndrome Global epidemiology of Campylobacter infection A clinical prognostic scoring system for Guillain-Barré syndrome Guillain-Barré syndrome in Asia A multicentre prospective study of Guillain-Barré syndrome in Japan: a focus on the incidence of subtypes Characteristics and acute rehabilitation of Guillain-Barré syndrome in Singapore Miller Fisher syndrome and Haemophilus influenzae infection Subtypes and prognosis of Guillain-Barré syndrome in southwest China Vaccine-preventable diseases, vaccines and Guillain-Barré syndrome Surgery and risk of Guillain-Barré syndrome: a French nationwide epidemiologic study Malignancy in Guillain-Barré syndrome: a twelve-year single-center study Guillain-Barré syndrome in Pakistan: similarity of demyelinating and axonal variants Guillain-Barré syndrome: clinical profile and management Quantifying the association between Campylobacter infection and Guillain-Barré syndrome: a systematic review Antecedent infections in Guillain-Barré syndrome: a single-center The immunopathogenesis of Miller Fisher syndrome Epidemiology of Campylobacter jejuni isolated from patients with Guillain-Barré and Miller Fisher syndromes in Japan Declining Guillain-Barré syndrome after campylobacteriosis control Increased rates of Guillain-Barré syndrome associated with Zika virus outbreak in the Salvador metropolitan area, Brazil Guillain-Barré syndrome following malaria Guillain-Barré's syndrome associated with Plasmodium falciparum malaria: role of plasma exchange Guillain-Barré syndrome in Plasmodium falciparum malaria Guillain-Barré syndrome associated with human immunodeficiency virus infection in Zimbabwe Acute inflammatory motor axonopathy associated with dengue fever Guillain-Barré syndrome following dengue fever and literature review Guillain-Barré syndrome in the course of dengue: case report Guillain-Barré syndrome associated with COVID-19 infection: a case report Guillain-Barré syndrome associated with SARS-CoV-2 Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? COVID-19 may induce Guillain-Barré syndrome Covid-19 associated Guillain-Barré syndrome: contrasting tale of four patients from a tertiary care centre in India COVID-19 and Guillain-Barré syndrome case report Covid-19 and Guillain-Barré syndrome: more than a coincidence! Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome & Neuroviruses Emerging in the Americas Study. Neurological implications of Zika virus infection in adults Guillain-Barré syndrome in SARS-CoV-2 infection: an instant systematic review of the first six months of pandemic Guillain-Barré syndrome spectrum associated with COVID-19: an up-to-date systematic review of 73 cases Genetics of Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): current knowledge and future directions Susceptibility to Guillain-Barré syndrome is associated to polymorphisms of CD1 genes FAS promoter polymorphisms and serum sFas level are associated with increased risk of nerve damage in Bangladeshi patients with Guillain-Barré syndrome Nutrition and immunity with emphasis on infection and autoimmune disease Outbreak of Guillain-Barré syndrome in Peru Guillain-Barré syndrome and healthcare needs during Zika virus transmission Guillain-Barré syndrome risk among individuals infected with Zika virus: a multi-country assessment Global trends in emerging infectious diseases Neurological disease in adults with Zika and chikungunya virus infection in Northeast Brazil: a prospective observational study Early Guillain-Barré syndrome associated with acute dengue fever The Zika virus epidemic in Brazil: from discovery to future implications Epidemiological survey of the incidence of Guillain-Barré syndrome in Harbin from 1997 to 1999. Chin Guillain-Barré syndrome in times of pandemics Assessment of current diagnostic criteria for Guillain-Barré syndrome Guillain-Barré syndrome in Bangladesh: validation of Brighton criteria Recent developments and future directions in Guillain-Barré syndrome Guillain-Barré syndrome in India: population-based validation of the Brighton criteria Clinical features and the validation of the Brighton criteria in Guillain-Barré syndrome: retrospective analysis of 72 hospitalized patients in three years Guillain-Barré syndrome associated with normal or exaggerated tendon reflexes The spectrum of antecedent infections in Guillain-Barré syndrome: a case-control study Recognizing Guillain-Barré syndrome in preschool children Clinical presentation and course of childhood Guillain-Barré syndrome: a prospective multicentre study Multidisciplinary care for Guillain-Barré syndrome Treatment dilemmas in Guillain-Barré syndrome Clinical outcome of Guillain-Barré syndrome with various treatment methods and cost effectiveness: a study from tertiary care center in South India: Yashoda GBS registry Guillain-Barré syndrome: surveillance and cost of treatment strategies -authors' reply Management of Guillain-Barré syndrome with plasmapheresis or immunoglobulin: our experience from a tertiary care institute in South India Risk factors for respiratory failure in Guillain-Barré syndrome in Bangladesh: a prospective study Reducing the economic burden in management of Guillain-Barré syndrome using modified plasmapheresis Inhibition of C1q, initiator of the classical complement cascade, by ANX005 for the treatment of Guillain-Barré syndrome: results from a phase 1b study Economics of AIDS and Access to HIV-AIDS Care in Developing Countries: Issues and Challenges Outcome of Guillain-Barré syndrome patients with respiratory paralysis Diagnosis and management of Guillain-Barré syndrome in ten steps Predictors for mechanical ventilation and short-term prognosis in patients with Guillain-Barré syndrome Prediction of respiratory insufficiency in Guillain-Barré syndrome ICU facilities scanty at government hospitals of Bangladesh. The Daily Star Guillain-Barré syndrome: natural history and prognostic factors: a retrospective review of 106 cases Guillain-Barré syndrome as a prominent cause of childhood acute flaccid paralysis in post polio eradication era in Egypt A systematic review of access to rehabilitation for people with disabilities in low-and middle-income countries Outcome and its predictors in Guillain-Barré syndrome Recovery patterns and long term prognosis for axonal Guillain-Barré syndrome Fatigue, pain, anxiety and depression in Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy Factors associated with long-term functional outcomes and psychological sequelae in Guillain-Barré syndrome Early recognition of poor prognosis in Guillain-Barré syndrome EGOS has a reduced capacity to predicts GBS prognosis in Northeast Brazil Markers for Guillain-Barré syndrome with poor prognosis: a multi-center study The utility of Guillain-Barré syndrome prognostic models in Malaysian patients A modified peripheral neuropathy scale: the overall neuropathy limitations scale Outcome measures in neuromuscular disease: is the world still flat? Improving fatigue assessment in immune-mediated neuropathies: the modified Rasch-Built fatigue severity scale Clinical profile, functional outcome, and mortality of Guillain-Barré syndrome: a five-year tertiary care experience from Nepal Clinical features of post-vaccination Guillain-Barré syndrome (GBS) in Korea All authors contributed substantially to the initial discussions of the article content and to review or editing of the manuscript before submission. N.P. conducted the literature search, and N.P. and Z.I. researched data for the article. N.P. and Z.I. wrote the first draft of the manuscript and S.E.L., Q.D.M., H.P.E. and B.C.J. contributed to subsequent versions. The authors declare no competing interests. Nature Reviews Neurology thanks T. Umapathi and the other, anonymous, reviewers for their contribution to the peer review of this work. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The online version contains supplementary material available at https://doi.org/10.1038/s41582-021-00467-y. GBs|CiDP Foundation international: https://www.gbs-cidp.org/