Abstract
Guillain–Barré syndrome (GBS) is an autoimmune polyradiculoneuropathy with diverse clinical subtypes, characterized by rapidly evolving motor weakness, sensory disturbances and areflexia. The global prevalence of GBS has been steadily increasing, with regional disparities. Mortality rates vary but remain elevated in patients requiring mechanical ventilation. This systematic review aimed to evaluate the predictive risk factors for the severity of the disease and poor short- and long-term outcomes of GBS. The literature search was conducted using the PubMed database by 2 independently working researchers. After a screening process of studies published before November 2023, a total of 109 articles were selected. Original articles, systematic and narrative reviews, meta-analyses, and editorials were selected based on their clinical relevance. The exclusion criteria included patients under 18 years of age, pregnant women and articles in languages other than English and Polish. Long-lasting GBS complications included pain, fatigue and persistent neurological deficits, affecting patients for years after recovery. Identifying the appropriate therapeutic methods, risk factors and prognoses of GBS at an early stage is crucial. Various risk factors for death and poor functional outcomes were found, regarding patient characteristics, the clinical course of GBS, laboratory and neurographic results, as well as treatment methods.
Key words: treatment outcome, risk factors, prognosis, Guillain–Barré syndrome
Introduction
Guillain–Barré syndrome (GBS) is an autoimmune inflammatory polyradiculoneuropathy affecting peripheral nerves.1 It is characterized by rapidly evolving ascending motor weakness, areflexia and sensory disturbances that develop within 4 weeks.2 Guillain–Barré syndrome often follows infections, but it can also occur after vaccinations, surgeries or during pregnancy.3 The main variants of GBS include acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and Miller–Fisher syndrome (MFS).2 Acute inflammatory demyelinating polyradiculoneuropathy manifests as a sensorimotor form that can co-occur with cranial nerve deficits and autonomic dysfunction. Acute motor axonal neuropathy is a pure motor form in which the cranial nerves are intact. Acute motor and sensory axonal neuropathy (AMSAN) is a condition that shares similarities with the AMAN pattern, but it additionally affects sensory nerves.4 Miller–Fisher syndrome is less common and is characterized by ataxia, ophthalmoplegia and areflexia.5
The age-standardized prevalence of GBS is the highest in high-income Asia Pacific and North American countries, especially Japan and Singapore. East Asia and Oceania have the lowest GBS prevalence rates.6 The AIDP type is significantly more common in Europe and North America, while AMAN occurs more frequently in East Asia.5
The prevalence of GBS has continued to increase globally over the years. In 1990, the global prevalence per 100,000 persons was 3.6%, and in 2019 it reached 9.5%.6 In a 2009 study, the global incidence of GBS was estimated between 1.1 and 1.8 cases per 100,000 persons/year.7 In the recent 2021 meta-analysis, the incidence of GBS among the cohort studies was higher and varied from 0.30 to 6.08 cases per 100,000 persons and 0.42 to 6.58 cases per 100,000 person-years.8 Guillain–Barré syndrome is slightly more frequent in men than in women and its incidence tends to increase with age.9
The mortality rates of GBS vary significantly between studies and range between 1–18%.10, 11, 12 They remain higher (12–20%) in patients requiring endotracheal intubation and mechanical ventilation (MV).13, 14
Guillain–Barré syndrome is associated with long-lasting complications, such as pain, fatigue, disability, and impaired psychosocial functioning.15 Persistence of moderate-to-severe pain was reported in different studies after 1 or 2 years in over 1/3 of patients.16, 17 Patients, after recovering from GBS, still report neurological deficits. Many studies described deficits in ambulation and sensation occurring 1 year after illness onset.18, 19 Motor and sensory disturbances were reported quite commonly even 10 years later.20 In a study by Durand et al., after 6 months, almost 1/3 of patients had a disability grade ≥2 (Plasma Exchange/Sandoglobulin Guillain–Barré Syndrome Trial Group, 1998: 0 = healthy, no signs or symptoms of Guillain–Barré syndrome; 1 = minor symptoms or signs and able to run; 2 = able to walk 5 m across an open space without assistance; 3 = able to walk 5 m across an open space with the help of 1 person and waist-level walking-frame, stick, or sticks; 4 = chairbound/bedbound: unable to walk as in 3; 5 = requiring assisted ventilation (for at least part of day or night); 6 = dead).21 In another study, at 3–5 years after GBS onset, 20% of patients had a disability grade of 2 and 10% had a disability grade of 3.22 In a recent long-term study, approx. 10% of patients exhibited disability by the end of the study period. Of these, 5% demonstrated moderate disability, while 5.2% exhibited severe disability.23
The outcomes of GBS differ between the GBS subtypes. A study by Zhang et al. found that the prognosis of AMAN patients was poorer than that of AIDP patients,24 which was confirmed in a 2020 study where AMAN was found to be an independent predictor of an unfavorable outcome.25 A recent 2022 study reported worse outcomes in patients with AMAN and AMSAN compared to those with AIDP.26 Patients with MFS usually have a good natural recovery, and almost no residual deficits were left at follow-up, regardless of the treatment.27
The pathophysiology of GBS is based on the phenomenon of molecular mimicry. Depending on the site on the nerve cell where the antibody attack occurs, GBS assumes a specific clinical form. The autoimmune process is usually initiated by an infection. Figure 1 shows these processes in a clinical form.
The figures were drawn with Procreate v. 5.3.3 (Savage Interactive, Hobart, Australia). Parts of the Figure 1 were made using pictures from Servier Medical Art, which is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/). The diagnosis and management of GBS should be based on guidelines published in 2023 by van Doorn et al.28 The diagnosis is established regarding the patient’s history and neurological, electrophysiological and cerebrospinal fluid (CSF) examinations. An alternative diagnosis for the weakness must be excluded.29, 30 Guillain–Barré syndrome should be taken into account in patients who have rapidly progressive symmetric motor weakness of the legs and/or arms in the absence of other apparent causes, especially if there is a history of recent diarrhea or respiratory infection.28 Patients with the classic sensorimotor form present with distal paresthesias or sensory loss, ascending weakness, and a loss of reflexes. Symptoms develop within no more than 4 weeks and in most patients within 2 weeks.28, 30, 31 Cerebrospinal fluid analysis is valuable and usually shows an elevated protein level and a normal cell count, known as albuminocytologic dissociation.32 In standard conduction velocity tests, prolongation of distal latencies, slowing of conduction velocities mostly in motor fibers, and prolongation or absence of F-waves are observed.33
Electrodiagnostic studies are also helpful in differentiating between the 4 subtypes of classical GBS: AIDP, AMAN, AMSAN, and MFS.34 The criterion for the diagnosis of AIDP is the electrophysiological confirmation of a decrease in the conduction velocity of 2 or more motor nerves, suggesting an immune-mediated demyelinating process involving the membrane of Schwann cells or myelin.35 Acute motor axonal neuropathy is distinguished from AIDP due to the occurrence of axonal involvement without demyelination. The diagnosis of AMAN is based on the finding of reversible conduction failure due to axonal conduction block at the nodes of Ranvier or the motor nerve terminal without axonal degeneration or extensive axonal degeneration.28 There are also rarer types of GBS, such as AMSAN and MFS. The first of them concerns changes, the basis of which lies in the axonal degeneration of both motor and sensory fibers. The latter is characterized by a characteristic triad of clinical symptoms, which includes ophthalmoplegia, ataxia and areflexia, which is closely related to the presence of specific antibodies against ganglioside GQ1b.36
It is currently believed that the best effects in GBS therapy are achieved through the use of intravenous immunoglobulin (IVIG) 0.4 g/kg within 2 weeks of the onset of symptoms for 5 days.37 Good results are also achieved by performing plasmapheresis in the amount of 4–6 treatments. The key variable influencing the effectiveness of therapy is the time of initiation of therapy, which should be started as soon as possible, up to 12 h after the onset of symptoms.38
Objectives
This study aimed to undertake a new review of the up-to-date literature concerning the risk factors regarding patient characteristics, the course of GBS, and laboratory and neurographic test results. The efficacy of the possible treatments was also discussed.
Materials and methods
A review of scientific articles published in the PubMed database between 1981 and 2023 was performed. Data were collected in September 2023 by 2 independently working researchers. The following filters were used in the PubMed database: ((GBS) OR (Guillain–Barré syndrome)) AND (long-term) AND ((disability) OR (outcomes) OR (mortality)), ((GBS) AND (risk factors)) and ((GBS) AND (predictors)) for a total of 1,384 results. Of these, 944 articles were removed after reviewing the title or abstract, since they were unrelated to the topic of the research. The exclusion criteria were patients under 18 years of age and pregnant women. Conference abstracts and articles in languages other than English and Polish were excluded as well. Ultimately, 73 articles were qualified for analysis. Additionally, 36 papers were used that did not appear in the automatic search but were considered relevant. The summary of the results for unfavorable outcomes is provided in Table 1. The summary of the studies mentioned in this review is provided in Table 2.39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92 Figure 2 depicts the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart of evaluated studies. All figures and tables were prepared manually Servier Medical Art and Procreate software.
Risk factors: Patient characteristics
Risk factors for death regarding patient characteristics are older age and pre-existing comorbidities, such as organ dysfunction (including cardiac and pulmonary disease), diabetes mellitus and coronary artery disease.39, 40, 41 In a study by Dhar et al., advanced age was the strongest predictor of poor outcomes.40, 42 Van den Berg et al. found that 73% of the deceased patients had a history of pulmonary or cardiac disease.43 This is consistent with other studies, in which mortality was significantly associated with underlying cardiopulmonary diseases.13, 44 A recent 2022 study found a correlation between dyslipidemia and the severity of GBS.45 Furthermore, the recent history of surgery is associated with an unfavorable short-term prognosis and disease severity.41
Risk factors: Clinical course of the disease
Several risk factors for death and poor functional outcome regarding the clinical course of GBS were found, including the severity of weakness at entry, MV, delay from onset of weakness to entry, voiding difficulties, and time to peak disability.43, 46, 47, 93 The time between onset of disease and death is highly variable. In a study by van den Berg et al., the median time was 76 days (ranging from 23–152 days). Sixty-seven percent of patients died in the recovery phase, 20% in the acute progressive phase and 13% during the plateau phase.43 The severity of the disease is usually assessed using the Medical Research Council (MRC) sum score or GBS disability score.94, 95 In a recent 2023 study, the best predictor of clinical rating scores using the Hughes Disability Scale (HDS) and Overall Neuropathy Limitation Scale (ONLS) was a low MRCSS on the 10th day of treatment.48 A study of Bangladeshi patients revealed that MV and the absence of ventilator support when it was required were risk factors for death. The unavailability of MV for patients with acute respiratory failure was identified as the most important risk factor that accounted for 20% of deaths.49 The need for MV is correlated with longer hospital stay and and reduced rate of recovery up to 1 year after the onset of disease.50 The probability of developing respiratory insufficiency within the 1st week can be assessed with the Erasmus GBS Respiratory Insufficiency Score (EGRIS).96 It employs time between the onset of weakness and admission, facial and/or bulbar weakness, and MRC scores to divide patients into 3 groups according to their risk. In 2023, Luijten et al. published a modified EGRIS, which requires less information for a prediction, can be used at multiple time points, and is used in less severe cases.97 The inability to walk unaided at 4 and 26 weeks in GBS patients can be predicted using the modified Erasmus GBS Outcome Score (mEGOS).98
Autonomic dysfunction, bulbar nerve involvement, papilledema, and neck flexor weakness have also been identified as factors associated with adverse outcomes in GBS patients.48, 49, 51 Bulbar palsy and neck flexor weakness are often correlated with respiratory compromise and the need for MV.51, 52 Durand et al. reported that bulbar palsy was present in 38% of ventilated patients and in 10% of non-ventilated patients,21 while Paul et al. found bulbar involvement in 92.5% of ventilated patients compared to 28.2% of non-ventilated patients.52
The Italian Guillain–Barré Study Group observed that the type of antecedent disorder influenced the chances of clinical recovery. Patients who experienced gastroenteritis prior to the onset of symptoms took the longest time to achieve clinical recovery, with an average duration of 292 days, whereas those with an upper respiratory infection averaged 193 days, and patients with influenza took an average of 123 days to recover.53 This was later confirmed in studies by van Koningsveld et al., Walgaard et al. and Khedr et al., in which preceding diarrhea was an unfavorable factor for recovery at 3 and 6 months.48, 54, 99 Moreover, coexisting cytomegalovirus (CMV) and herpes simplex virus (HSV) infections on admission may correlate with a higher risk of respiratory failure.55
The study by Dhar et al. stated that for the occurrence of severe complications, the risk difference did not reach statistical significance in terms of final recovery. However, serious ICU complications were associated with a longer time to recover.40 A recent 2023 study found that pulmonary infections can be used as an independent predictor for a poor early prognosis in patients with GBS.56
A prolonged hospital stay was found to be significantly associated with a poorer prognosis. This may be attributed to the higher incidence of complications commonly associated with prolonged hospital stays, including pneumonia, sepsis and respiratory distress syndrome (RDS).58, 58
Wang et al. found that the chief complaints of GBS patients could be clinic predictors of disease severity, the need for MV and short-term outcomes. Patients presenting with weakness as a main complaint were more likely to experience a severe disease progression and have a worse short-term outcome, while a chief complaint of numbness and cranial nerve involvement was a promising predictor.59
In a study conducted by Lopez–Hernandez et al., the AMAN subtype was found to be a predictor of worse short-term outcomes.25
Risk factors: Laboratory tests
For the clinician, the most important factor is the susceptibility of the GBS variant to standard treatment regimens. A direct predictor of therapeutic problems is the need for MV. Patients who showed the presence of anti-GD1a/GD1b and/or anti-GD1b/GT1b antibodies were most likely to have GBS with impaired spontaneous breathing.60 The presence of antibodies against ganglioside complexes (GSCs) also determines the occurrence of symptoms such as ophthalmoplegia and lower cranial nerve deficits.60 Gangliosides such as GD1a may interact with GM1 in cell membranes to regulate the binding and biological activity of some anti-GM1 antibodies. However, studies have shown that the high specificity of anti-GM1 antibodies in GBS is a factor defining the disease severity.61 It is worth paying attention to the presence of anti-GM1 antibodies (immunoglobulin g; IgG) in patients with GBS due to the selection of treatment. Intravenous immunoglobulins have been proven to be more effective than plasmapheresis in patients with these antibodies.62 Studies also show that monitoring anti-GM1 IgM levels can predict clinical status and recovery in patients with GBS.63
Despite the relatively small number of available studies, it should be remembered that the presence of the tumor necrosis factor alpha (TNF-α) 308A allele may be a moderate risk factor for GBS.64 Additionally, it has been noted that GBS patients show abnormal expression of immune-related genes. Identification of GBS risk alleles may help identify risk groups, avoid triggers and design personalized therapeutic approaches.65
Moreover, researchers are using serum C3 complement levels as a biomarker in GBS. Higher C3 levels are associated with longer hospitalizations and more frequent treatment-related fluctuations. These patients also presented lower MRCSS and higher GBS disability scores (GBSDS). The clinical severity of GBS occurs with longitudinal change in C3 levels.100
Other important parameters that will indicate difficulties in treatment are sodium, albumin, neutrophil/lymphocyte ratio (NLR), C-reactive protein (CRP), and protein concentrations in the CSF.48, 66 Hyponatremia occurs during more severe GBS episodes but is not directly correlated with or directly specific to them. Its occurrence is probably related to the disturbance of body homeostasis.66, 67, 68 However, analyses have proven a relationship between the results of the HDS and the ONLS and sodium concentrations in patients with a poor prognosis.48, 67, 69 Sodium levels should be monitored, especially in patients with other risk factors, as they can directly affect outcomes.70
Low serum albumin levels accompanied more severe forms of GBS. Researchers believe that their level is a protective factor. Serum albumin plays a strong antioxidant role by inhibiting free hydroxyl radicals that are produced in the process of inflammation, demyelination and axonal damage. Therefore, it was found to be beneficial to administer human albumin in patients with GBS and hypoalbuminemia.55, 66
Neutrophil/lymphocyte ratio and CPR are considered non-specific parameters of blood tests. However, they can confirm the diagnosis, and at the end of the 1st month of the disease, their levels have a prognostic value for a more severe course.66, 71, 72 Neutrophil/lymphocyte ratio can be considered an independent risk factor for GBS.73, 74
According to studies, a CRP >5 and protein-to-albumin ratio (CAR) >0.21 are independently associated with the occurrence of respiratory failure in patients with GBS, while a CRP >5 and CAR >0.19 predict poorer short-term outcomes in patients with GBS. The researchers suggest measuring the CAR on admission as it may be a better predictor of complications such as risk of respiratory failture than only CRP results.75
Elevated protein levels in the CSF are detected during inflammation of the nervous system. It has been noted that the lower the protein values at the beginning of a GBS episode, the better the prognosis.76 High values may indicate destruction of the blood–nerve barrier.77 It has been observed that there are higher absolute values of CSF total protein (CSF-TP) in classic sensorimotor GBS and local GBS compared to MFS and motor GBS. However, due to the weak correlation of CSF-TP and disability in GBS, it cannot be used as a factor for the modification of treatment plans.78
Diabetes exacerbates the clinical and electrophysiological symptoms of GBS and affects long-term disability due to the presence of chronic low-grade inflammation (elevated inflammatory markers: CRP, TNF-α and interleukin 6; IL-6).79 Higher fasting blood glucose (FPG) levels on admission were associated with a poorer short-term prognosis as measured using the MRCSSs and GBS disability scale at discharge. However, the development of disability is not related to blood HbA1c or CSF glucose concentrations.80 Additionally, some diabetic patients may have pre-existing nerve damage, which exacerbates the reduced rate of nerve regeneration. It is also noted that patients with GBS and diabetes are more likely to develop the axonal form of the disease, and the electrophysiological changes in these patients are more pronounced.81
A significant relationship was demonstrated between folate deficiency at the time of admission and the duration of GBS progression. The exact role is unclear, but it is known that folate is essential for peripheral nerves, and its deficiency is associated with axonal sensory polyneuropathy.82
Long-term symptoms of GBS are caused by axonal damage. The presence of elevated levels of neurofilaments (NfH), a biomarker indicative of axonal damage, has been demonstrated to possess prognostic value in the context of GBS. Additionally, CSF NfH levels correlated with F scores and MRCSSs. These were higher in patients with neurophysiological features of axonal degeneration. The cutoff point for poorer motor and functional outcomes was defined as >0.73 ng/mL of NfH in the CSF.83 Additionally, research shows that neurofilament light protein (NFL) should be included as an early indicator of patients requiring extensive medical and rehabilitation interventions for the long term. Patients who are severely disabled at the onset of GBS but have low concentrations of NFL in their CSF are considered to have a significantly greater chance of recovery.84, 85
Risk factors: Neurographic tests
Neurophysiological tests can be successfully used to establish the initial diagnosis. Attempts to use them to determine the prognosis raises many doubts. There is no shortage of voices claiming that the lack of electrical excitability of the motor nerves and the lack of electrical activity in the quadriceps femoris muscle on the 10th day after the onset of the disease are independent factors for a more severe course and more difficult treatment.101 However, more recent studies have shown that the diagnostic value of neurophysiological methods increases in proportion to the time since the onset of the disease.102 Besides the quadriceps femoris muscle, deltoid muscle strength may also have a predictive value.86
Studies show that patients with markedly attenuated compound muscle action potentials (CMAPs), inexcitable motor nerves, and denervation changes on electromyography will be required to undergo MV. Nevertheless, the most prevalent abnormalities observed in both patients requiring and not requiring ventilation are abnormal H reflexes and F waves.87, 88
Another predictive factor was found to be the intraepidermal nerve fiber density (IENFD), which correlates (decreases early and stays low for a long time) with pain intensity in the acute phase and may predict long-term disability.89 In USG, there can be detected vagus nerve or cervical spinal nerve hypertrophy and regression of these changes within 6 months indicates a better prognosis.90
Risk factors: Treatment course
In the treatment of GBS, it is important to use IVIGs or plasmapheresis, which, according to researchers, maximizes survival potential.103, 104 There are also no significant differences between the use of plasma exchange and IVIG. Nevertheless, control using the ONLS indicates the advantage of treatment with IVIG.48, 91 Long-standing improvements may not be directly related to IVIG treatment but are caused by self-limitations. Despite this, studies prove that this treatment had a long-term effect on both mild and moderate-to-severe GBS.92 It also does not seem that more intensive treatment has a significant impact on improvement in patients with advanced degrees of disability. Studies have shown that patients unable to walk on their own did not show improvement after an additional course of immunotherapy.105
Limitations
This systematic review has several limitations. First, only articles in English and Polish were included. No searches were made for scientific reports in other languages. Furthermore, the simultaneous appearance of some conditions or diagnostic test results and GBS episodes can be coincidental. Moreover, the heterogeneity of patients makes it difficult to combine and interpret the results, limiting conclusions. It was not possible to fully verify this data due to insufficient information about the patients.
Conclusions
This review of the literature focused on identifying prognostic factors associated with a worse outcome in patients with GBS. Scales to identify patients at high risk of mortality have also been developed to assess the course of GBS. Knowledge of these prognostic factors may, in the future, make it possible to modify the current treatment regimens for these patients.