Guillain Barre syndrome

6.09.2.3.1.1 Overview

GBS is a collection of acute or sometimes subacute, self-limiting postinfectious autoimmune polyneuropathies of the PNS. GBS involves both myelin and axons, and results in flaccid paralysis of at least two limbs. Other symptoms can include generalized weakness, areflexia, and usually numbness, a varying degree of sensory disturbances, and involvement of cranial nerves. Weakness of respiratory muscles renders about 25% of patients respirator-dependent. Symptoms begin 1-3 weeks after various infections, and peak from a few days up to 4 weeks, with patients recovering spontaneously. Recovery can take weeks or years. Many patients have persistent fatigue, and some are unable to walk 1 year after onset; the younger the patient, the better the prospect for complete recovery. Mortality rates range from 3% to 12%, with patients dying of complications during the acute stage.

GBS patients can be subtyped on the basis of antecedent infection, anti-ganglioside antibodies, and neurological deficits (see Table 1). GBS subtypes include acute inflammatory demyelinating neuropathy (AIDP), which accounts for about 90% of GBS cases, atypical presentations of AIDP, Miller-Fisher syndrome, in which weakness is restricted to extraocular and other craniobulbar muscles, and the axon loss variants - including acute motor axonal neuropathy (AMAN), which occurs in up to 10% of patients. Some patients exhibit clinical features typical of more than one subtype - so-called overlap syndromes. Making a rapid diagnosis is often difficult as there are many mimics of GBS,9 and CSF may not be diagnostic for up to 2 weeks.

The AIDP subtype is characterized by an infiltration of endoneural capillaries by lymphocytes and a macrophage-mediated demyelination of both sensory and motor nerves in a segmental fashion with deposition of complement activation products on Schwann cell surface membranes. AMAN, in which motor axons appear to be the target of immune attack, is characterized by Wallerian-like degeneration without significant demyelination and with little or no lymphocytic infiltration.

While GBS occurs throughout the world, the axonal forms of the disease are much less common in Europe and North American, and more common in China, Japan, India, and Central America. Contrary to many autoimmune diseases, males are more commonly affected than females.10 Age distribution is bimodal - with peaks in young adults and the elderly. There are no reliable serological markers.

6.09.2.3.1.2 Pathogenesis

GBS etiology has a clear environmental component: about two-thirds of GBS patients have antecedent gastrointestinal or respiratory infections by Campylobacter jejuni, Epstein-Barr virus, cytomegalovirus, or Mycoplasma pneumonia. The most frequently identified cause of GBS is C. jejuni infection - identified in up to 41% of patients. Patients with antecedent C. jejuni infection are more likely to require ventilation and have prolonged severe disability.10

Clinical data support the hypothesis that autoantibodies are involved in GBS pathogenesis: the efficacy of plasma exchange (PE) and intravenous immunoglobulin (IVIg) therapies and the case of flaccid paralysis in a newborn of a mother with GBS. There is also strong support for a specific role for ganglioside antibodies: the identification of GBS-like symptoms in some patients treated with gangliosides; approximately 40% of GBS patients have anti-ganglioside antibodies in their plasma; disease subtypes or symptoms correlate with the ganglioside antibody subtype, as well as with the differential expression of those subtypes in the PNS; and rabbits sensitized with C. jejuni lipooligosaccharide developed anti-GMl IgG antibody, flaccid limb weakness, and peripheral nerve pathology identical to GBS.11 The last study provides the strongest and most direct evidence that at least some types of GBS are the result of carbohydrate mimicry between an infectious agent and peripheral nerve ganglioside epitopes.12

Although gangliosides are present in both CNS and PNS, GBS appears to affect only the PNS. Thin-layer chromatogram immunostaining data suggest that antibodies from some patients may recognize ganglioside complexes, but have little or no reactivity for individual gangliosides; patients with these antibodies tend to have severe disabilities and cranial nerve deficits.13

Other data suggest possible functions of ganglioside antibody in GBS pathogenesis: IgG ganglioside antibody from GBS patients recognizes antigens at the node of Ranvier and the motor endplate presynaptic terminal, and in vitro experiments with rodent tissues demonstrate reversible conduction blockade with GM1 ganglioside monoclonal antibody.11 In addition, anti-GM1- or GD1a-specific IgG containing sera from GBS patients induce leukocyte inflammatory functions such as degranulation and phagocytosis via FcgR.14

Based on these findings, a pathogenetic sequence has been proposed for GBS with antecedent C. jejuni infection: infection by C. jejuni carrying a complex ganglioside-like lipooligosaccharide induces - in some patients - high production of anti-ganglioside IgG that binds to complex ganglioside on motor axons, leading, in turn, to macrophage-mediated and complement-dependent axonal degeneration.11'15

Estimates of the number of cases of C. jejuni infection complicated by the occurrence of GBS are one in 1000 or less, suggesting a role for host genetic factors in GBS etiology. The search for genetic factors revealed polymorphisms in the promoter region of Fas and in the gene for FcgRIII in a West European population that may represent mild disease-modifying factors in GBS.16,17 While these Fas and FcgRIII polymorphisms do not differ between GBS patients and controls, and thus do not represent general susceptibility factors for GBS, there does appear to be a weak association with the presence of anti-ganglioside antibodies and disease severity, respectively.

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