What are the causes of Guillain-Barré Syndrome (GBS)?

Causes of Guillain-Barré Syndrome

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, accounting for 30-32% of cases globally and up to 60-70% in some regions. 1, 2

Primary Infectious Triggers

Bacterial Pathogens

• Campylobacter jejuni is the most frequently identified trigger worldwide and causes more severe disease with prolonged disability compared to other triggers 1, 2, 3
• Mycoplasma pneumoniae is another bacterial trigger, though less extensively investigated than C. jejuni 4, 3
• Haemophilus influenzae has been associated with GBS but remains less well-characterized 4

Viral Pathogens

• Cytomegalovirus and Epstein-Barr virus typically precede the demyelinating and sensorimotor forms of GBS 4, 3
• Zika virus caused a 20-fold increase in GBS cases during the 2013-2014 French Polynesia outbreak, though only ~2 in 10,000 infected patients develop GBS 4
• SARS-CoV-2 has been associated with GBS, with 77-80% showing demyelinating electrophysiological subtype 4

Other Vector-Borne Viruses

• Chikungunya and dengue viruses (transmitted by Aedes mosquitoes) have been associated with surges in GBS cases 4
• Enterovirus infection was linked to a GBS outbreak in Peru in 2018 4

Clinical Presentation of Antecedent Events

Respiratory Infections (Most Common in Western Countries)

• Upper respiratory tract infections are the most common antecedent events, occurring in 22-53% of cases in Europe, North America, South America, and parts of Asia 1
• Respiratory infections are even more frequent in pediatric GBS cases (50-70%) 1

Gastrointestinal Infections (Regional Variation)

• Gastroenteritis is the most frequent preceding event in India and Bangladesh (36-47% of cases) 1
• This regional pattern correlates with higher prevalence of C. jejuni infection in these areas 1

Pathophysiological Mechanism

Molecular Mimicry

• The fundamental mechanism is molecular mimicry between microbial surface components and peripheral nerve structures, triggering cross-reactive antibodies that damage myelin or axons 2, 3
• 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 4, 2
• Pathogenic lipo-oligosaccharides trigger the innate immune system via Toll-like-receptor (TLR)-4 signaling 3

Autoimmune Response

• The infection triggers an autoimmune response causing demyelination and axonal degeneration of peripheral nerves and nerve roots 1
• In acute inflammatory demyelinating polyneuropathy (AIDP), demyelination occurs, whereas in acute motor axonal neuropathy (AMAN), structures of the axolemma are affected 3

Host Susceptibility Factors

Genetic Factors

• Polymorphisms in the TNF gene (encoding tumor necrosis factor) and MBL2 gene (encoding mannose-binding protein C) have been associated with GBS susceptibility 4, 1
• These genetic variations may influence the patient's susceptibility to producing cross-reactive antibodies 4

Nutritional Status

• Poor nutritional status and malnutrition alter dysfunctional immune responses implicated in autoimmune disease pathogenesis 4, 1

Low Overall Risk Despite Widespread Exposure

• Despite widespread exposure to triggering infections, only a small fraction develop GBS: only 1 in 1,000-5,000 patients with C. jejuni infection develop GBS within the subsequent 2 months 4, 1
• One factor determining this low risk is the requirement for carbohydrate mimicry, which is not present in all C. jejuni strains 4

Geographic and Regional Patterns

Subtype Distribution

• AIDP is the most common subtype in Europe and North America (83-90% of GBS cases) 1, 2
• Axonal forms are more common in Asia, particularly where C. jejuni infection is prevalent 2

Severity Correlation

• In countries where C. jejuni infection is more common, approximately 80% of patients present with severe GBS (disability score >2) compared to 40-60% in regions where AIDP is more prevalent 1, 2

Common Pitfalls and Clinical Caveats

• Temporal relationship matters: Symptoms of infectious disease should occur within 4 weeks preceding the onset of weakness 1
• Not all infections lead to GBS: The requirement for specific molecular mimicry explains why only a tiny fraction of infected individuals develop GBS 4
• Regional epidemiology affects clinical presentation: The distribution of GBS subtypes correlates with the prevalence of specific infectious triggers in different regions 1
• Emerging disease hotspots: Regions at lower latitudes (sub-Saharan Africa, parts of Asia) where wild animals and arthropod vectors reside are at particular risk for new outbreaks of GBS due to vector-borne diseases 4