What are the etiology, pathogenesis, clinical features, and risk factors of Guillain-Barré Syndrome (GBS)?

Guillain-Barré Syndrome: Etiology, Pathogenesis, Clinical Features, and Risk Factors

Etiology

Guillain-Barré syndrome is an autoimmune polyradiculoneuropathy triggered by preceding infections in approximately two-thirds of cases, with Campylobacter jejuni being the single most important pathogen worldwide. 1

Infectious Triggers

• Campylobacter jejuni is the most frequently identified trigger globally, accounting for 30-32% of cases in most regions and up to 60-70% in some areas 2, 3
• Respiratory infections are the most common antecedent events (22-53% of cases) in Europe, North America, South America, and parts of Asia, and even more common in pediatric cases (50-70%) 2
• Gastroenteritis is the most frequent preceding event in some regions like India and Bangladesh (36-47%) 2

Six Pathogens with Established Temporal Association

The following pathogens have been confirmed in case-control studies 1:

• Campylobacter jejuni
• Cytomegalovirus
• Hepatitis E virus
• Mycoplasma pneumoniae
• Epstein-Barr virus
• Zika virus

Other Triggers

• Vaccines: Only the 1976 "swine" influenza vaccine showed a clear epidemiological link (7.3-fold increased risk); subsequent influenza vaccines show minimal association (approximately one additional case per million vaccinations) 1
• Immunobiologicals: Tumor necrosis factor antagonists, immune checkpoint inhibitors, and type I interferons have been reported in case series 1
• Absence of antecedent illness does not exclude GBS, as infections can be subclinical 1, 4

Pathogenesis

The fundamental mechanism is molecular mimicry between microbial surface components and peripheral nerve structures, triggering cross-reactive antibodies that damage myelin or axons. 1, 2

Molecular Mimicry Mechanism

• C. jejuni-related GBS: Structural similarities between C. jejuni lipo-oligosaccharides and human nerve gangliosides (GM1, GM1b, GD1a, GalNAc-GD1a) result in cross-reactive antibodies that activate complement and damage nerves 1, 5
• Axonal forms (AMAN/AMSAN): Antibodies target gangliosides expressed on the motor axolemma, causing axonal degeneration 5, 3
• Demyelinating form (AIDP): Immune reactions against Schwann cells or myelin components cause demyelination, though exact target molecules remain unidentified 5

Pathogen-Specific Patterns

• C. jejuni infections predominantly (but not exclusively) trigger axonal GBS subtypes 1
• Viral infections (cytomegalovirus, Epstein-Barr virus) typically precede demyelinating and sensorimotor forms, though the immunopathogenesis remains incompletely understood 1
• SARS-CoV-2-associated GBS: 77-80% had demyelinating subtype and ~70% had classic sensorimotor GBS, though data are limited 1

Why Only Few Develop GBS

Despite widespread exposure to triggering pathogens, only a tiny fraction develop GBS 1, 2:

• Only 1 in 1,000-5,000 patients with C. jejuni infection develop GBS within 2 months 1, 2
• Carbohydrate mimicry is not present in all C. jejuni strains 1
• Genetic factors: Polymorphisms in TNF and MBL2 genes are associated with GBS susceptibility 1, 2
• Nutritional factors: Malnutrition alters immune responses implicated in autoimmune disease pathogenesis 1, 2

Clinical Features

GBS typically presents with rapidly progressive bilateral weakness beginning in the legs and ascending to the arms and cranial muscles, with most patients reaching maximum disability within 2 weeks. 1, 4

Classic Presentation

• Progressive weakness: Bilateral limb weakness that progresses over days to 4 weeks maximum 1, 5
• Sensory symptoms: Sensory signs typically accompany motor weakness 1
• Areflexia: Loss of deep tendon reflexes is characteristic 1
• Temporal profile: Most patients reach maximum disability within 2 weeks; if maximum disability occurs within 24 hours or after 4 weeks, consider alternative diagnoses 4

Clinical Variants

GBS variants are rarely "pure" and often overlap 1:

• Pharyngeal-cervical-brachial weakness: Affects oropharyngeal muscles, neck, and upper limbs 1
• Paraparetic variant: Predominantly affects lower limbs 1
• Miller Fisher syndrome (MFS): Ophthalmoplegia, areflexia, and ataxia (associated with anti-GQ1b antibodies) 1
• Acute motor axonal neuropathy (AMAN) and acute motor sensory axonal neuropathy (AMSAN): Axonal subtypes 1, 4

Severe Complications

• Respiratory failure: Occurs in approximately 20% of patients, requiring mechanical ventilation 1, 6
• Autonomic dysfunction: Cardiac arrhythmias and blood pressure instability can occur 1, 6
• Mortality: 3-10% even with optimal care, primarily from cardiovascular and respiratory complications 1, 6

Disease Course

• Progressive phase: Days to 4 weeks maximum 1
• Plateau phase: Days to weeks or months 1
• Recovery phase: 60-80% of patients walk independently at 6 months; recovery is most extensive in the first year but can continue beyond 5 years 1, 4
• Treatment-related fluctuations (TRFs): Occur in 6-10% of patients who deteriorate after initial stabilization 4
• Relapses: Rare, occurring in 2-5% of patients 1, 4

Pediatric Considerations

Young children (<6 years) may present atypically with 4:

• Poorly localized pain
• Refusal to bear weight
• Irritability
• Unsteady gait

Risk Factors

Demographic Factors

• Male sex: Men are more frequently affected than women 1, 5
• Increasing age: Incidence increases with age, though all age groups can be affected 1
• Advanced age: Associated with higher mortality and poorer outcomes 6

Geographic and Environmental Factors

• Regional infection patterns: Geographic differences in clinical phenotypes correlate with rates of preceding infections 1, 2
• AIDP predominance: 83-90% of GBS cases in Europe and North America 2
• Axonal forms: More common in Asia, particularly where C. jejuni infection is prevalent 2, 5
• Severity correlation: In countries where C. jejuni is more common, approximately 80% present with severe GBS (disability score >2) compared to 40-60% in AIDP-predominant regions 2

Disease-Related Risk Factors

• Severe disease at onset: Associated with poorer prognosis 6
• Axonal subtypes (AMAN/AMSAN): Generally have poorer outcomes than demyelinating forms (AIDP) 6
• C. jejuni-triggered GBS: Usually more severe than GBS due to other causes 3
• Requirement for mechanical ventilation: Associated with poorer long-term outcomes 6

Outbreak Scenarios

• Zika virus outbreaks: 20-fold increase in GBS cases during French Polynesia outbreak (2013-2014); 3.2-5.1 times increase in Latin America and Caribbean (2014-2016), though only ~2 in 10,000 infected patients developed GBS 1
• C. jejuni epidemics: Surges in GBS cases in China (2007) and Mexico (2011) 1
• Enterovirus epidemics: GBS outbreak in Peru (2018) 1