Aetiology

Guillain-Barre syndrome (GBS) is characterised by an immune-mediated attack on the myelin sheath or Schwann cells of sensory and motor nerves. This is due to cellular and humoral immune mechanisms, frequently triggered by an antecedent infection.

Although genetic predisposition has not been fully established, the acute motor axonal neuropathy (AMAN) type of the disease occurs more commonly in Japan and China than in North America or Europe. Polymorphisms in genes encoding macrophage mediators (matrix metalloproteinase-9 and tumour necrosis factor-alpha) have been associated with severe weakness and poorer outcome in patients with GBS.[27] One meta-analysis suggested an association between GBS and FcgammaRIIa gene polymorphisms, and to a lesser extent with exon 2 of CD1E polymorphism, in white people.[28] 

Two-thirds of patients with GBS have had infections in the 6 weeks before symptom onset, most commonly upper respiratory tract infection or gastroenteritis. The acute infectious illness is usually viral (cytomegalovirus [CMV], Epstein-Barr virus [EBV], hepatitis E), but sometimes bacterial (Campylobacter jejuni, Mycoplasma species). The most commonly identified infectious triggers include C jejuni (in 13% to 39% of cases), CMV (5% to 22%), EBV (1% to 13%), and Mycoplasma pneumoniae (5%).[29][30][31]C jejuni infection precedes about 60% to 70% of AMAN and acute motor-sensory axonal neuropathy (AMSAN) cases and up to 30% of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) cases.[32][33]

GBS has been demonstrated in patients with confirmed coronavirus disease 2019 (COVID-19) and other human coronavirus infections.[34] All variants of GBS have been reported in COVID-19 patients.[23][24][25] The median interval between onset of COVID-19 symptoms and development of GBS was 11.5 days and 14 days in two systematic reviews.[23][25] This time interval suggests a post-infectious immune-mediated mechanism, but the details have yet to be established.[23][35]

Immunisations have been proposed to trigger GBS, but this suggestion is controversial, and was based primarily on data relating to the no longer used swine influenza vaccines (US in 1976) and the rabies vaccine containing brain material.[36][37] However, one study found no evidence of increased risk of GBS after seasonal influenza vaccine, and cohort studies found no risk of GBS following meningococcal conjugate vaccine A, C, Y, and W135 (MCV4).[38][39]

Epidemiological evidence indicates that the relative risk of GBS after immunisation is far lower than that following an infectious disease, especially for influenza.[40][41] There is a comparatively higher risk for pandemic vaccines than for seasonal vaccines.[42] Similarly, there are occasional case reports of GBS associated with vaccination against COVID-19, but considering the number of vaccinations across the globe this is likely to be a relatively rare occurrence.[26]

Cases of GBS were reported following the outbreak of Zika virus in 2013, possibly secondary to molecular mimicry, with a proposed putative role for gangliosides.[43][44][20][45] Several other mosquito-borne viral infections such as dengue, chikungunya, and Japanese encephalitis have also been linked to GBS.[46][47][48][49]

Pathophysiology

Guillain-Barre syndrome (GBS) is an autoimmune disorder in which antibodies to gangliosides play an important role. They trigger an attack on various components of peripheral nerve myelin and sometimes even the axons.[50][51] The mechanism for this is unclear but may be a consequence of molecular mimicry, whereby antibodies or T cells stimulated by antigenic epitopes on the infecting microbe cross-react with neural epitopes.[52] Host-generated antibodies against GM1-, GD1a-, GalNac-Gd1a-, and GD1b-related gangliosides are strongly associated with a subtype of AMAN, AMSAN, and Miller-Fisher syndrome (MFS).[17][53][54][55][56][57] AMAN is strongly associated with antibodies against GM1, GD1a, GalNac-GDa1, and GD1b.[53][54][58][59]

Pure sensory GBS may be associated with antibodies against GD1b.[9] Ganglioside complexes have been found to influence the phenotype. Antibodies against GD1a/GD1b or GD1b/GT1b may cause severe GBS, and antibodies against complexes containing GQ1b or GT1a are more likely to cause ophthalmoplegia in both GBS and MFS patients.[60]

In C jejuni-related infections, carbohydrate mimicry between the bacterial capsular lipooligosaccharide and specific myelin gangliosides and glycolipids is thought to induce antibodies against myelin.[61][62]

An immune cascade occurs in AIDP with early lymphocytic infiltrates in spinal roots and peripheral nerves. Subsequent macrophage-mediated segmental stripping of myelin occurs leading to segmental demyelination and mononuclear cellular infiltration.[5] Segmental loss of the insulating properties causes profound defects in the propagation of electrical nerve impulses, resulting in conduction block and the functional correlate of flaccid paralysis.[63] Once the immune reaction stops, repair and remyelination promptly begin, which correlate with a quick and, in most cases, complete recovery from the flaccid paralysis.[5]

AMAN can be differentiated from AIDP by autopsy findings of axonal denervation of motor and sensory nerves with no demyelination and minimal inflammation.[64][65] The earliest demonstrable pathological change seems to be the binding of IgG and activated complement components to axolemma at nodes of Ranvier in large motor fibres.[66] Macrophages become attracted to these nodes and track underneath the detached myelin lamellae along the periaxonal space. This dissects the axon from the overlying Schwann cell and compact myelin. Axolemmas in contact with invading macrophages are focally destroyed, while axons show progressive denervative changes to the point of total disintegration.[65]C jejuni strains associated with the AMAN pattern of GBS are known to have GM1-like epitopes in the liposaccharide membrane.[7] Pathological studies suggest severe and selective loss of terminal motor axons, whereas the distal sensory fibres are completely intact.[67][68]

Classification

Variants of Guillain-Barre

GBS is classified according to symptoms and is divided into axonal and demyelinating forms.

  • Sensory and motor: AIDP (most common) or AMSAN.[5]

  • Motor: acute motor demyelinating neuropathy or AMAN.[5]

  • Miller-Fisher syndrome: ophthalmoplegia, ataxia, and areflexia (also referred to as Fisher's syndrome).

  • Bickerstaff's brainstem encephalitis: similar to Miller-Fisher syndrome but also includes altered consciousness (encephalopathy) or hyper-reflexia, or both.[6]

  • Pharyngeal-cervical-brachial: acute arm weakness, swallowing dysfunction, and facial weakness.[5]

  • Acute pandysautonomia: diarrhoea, vomiting, dizziness, abdominal pain, ileus, orthostatic hypotension and urinary retention, bilateral tonic pupils, fluctuating heart rate, decreased sweating, salivation, and lacrimation.[7][8]

  • Pure sensory: acute sensory loss, sensory ataxia, and areflexia but no motor involvement.[9]

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