Immunopathology of Guillain- Barré syndrome. L. Magy Service de Neurologie Centre de Référence 'Neuropathies Périphériques Rares' CHU Limoges, France

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1 Immunopathology of Guillain- Barré syndrome L. Magy Service de Neurologie Centre de Référence 'Neuropathies Périphériques Rares' CHU Limoges, France

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3 What is Guillain-Barré syndrome? An immune-mediated peripheral neuropathy typically occurring after an infectious disease and characterized by: An ascending flaccid paralysis of acute onset, a plateau phase of variable duration and a (usually slow) recovery phase Sensory disturbances (pure motor possible) Possible respiratory distress Occasional cranial nerve and autonomic involvement Elevated CSF protein Nerve conduction findings suggestive of peripheral nerve involvement (demyelinating or axonal)

4 Diagnostic criteria for the classical form of GBS Fokke et al. Brain 2014

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6 Nerve lesions in GBS

7 GBS as a post-infectious disease GBS typically occurs after an infectious disease 2/3 of patients report symptoms of infection before GBS (respiratory, gastrointestinal) Campylobacter Jejuni, CMV, EBV, Mycoplasma Pneumoniae, Haemophilus Influenzae, Influenza A, Hepatitis E The immune response generates antibodies that crossreact with gangliosides at nerve membranes van den Berg et al. Nat Rev Neurol 2014

8 GBS as an epidemic disease GBS occurred as epidemics in northern China in summer months The neurophysiological and pathological picture was unusual with evidence of primary axonopathy Most of the patients had evidence of antibodies against Campylobacter Jejuni Some had a quick recovery, others had a poor outcome

9 A major breakthrough in the understanding of GBS pathogenesis J Exp Med 1993

10 Glycolipids involved in immunemediated neuropathy Gangliosides are very highly concentrated in the nervous system Anti-ganglioside antibodies are frequently found in patients with GBS (and other immunemediated neuropathies) To some extent, these Abs are linked to the clinical/neurophysiological/pat hological phenotype To date, this does not translate into therapeutic strategies Willison & Yuki Brain 2002

11 Two main forms of GBS: AIDP and AMAN Kuwabara & Yuki Lancet Neurol 2013

12 Pathogenesis of GBS The infectious agent triggers an immune response Molecular mimicry induces a crossreaction with Abs towards nerve gangliosides and other unknown targets The complement cascade is supposed to play a key role Macrophages are the final effectors of nerve lesions The exact role of lymphocytes in nerve is poorly understood van den Berg et al. Nat Rev Neurol 2014

13 Why do some people develop GBS (and others do not)? The infectious agent matters The occurrence of anti-ganglioside Abs in GBS is strain-dependent Some strains of C. Jejuni induce GBS and others do not A predisposed host matters Dendritic cell response to C. Jejuni is variable between, but not within, individuals Intrinsic factors determine the magnitude of Toll Like Receptor 4 innate response

14 Treatment of GBS Supportive ICU +++ Respiratory support! Targeting inflammation / autoimmunity Approved Intravenous Immunoglobulin (IVIg) Expensive Plasma Exchange (PLEX) ICU and other facilities needed Promising Targeting complement Eculizumab effective in animal models

15 Guillain-Barré syndrome and Zika virus infection: what do we know so far? A recent case-control study (involving 42 patients with GBS) showed that there is a strong association between Zika virus infection and GBS The clinical phenotype is characterized by a rapid evolution (ascending in 6 days and a short plateau phase of 4 days) Prognosis seems good (57% able to walk independently at 3 months and no one died) but respiratory assistance required in 29% at some point Electrodiagnostic findings are suggestive of the AMAN type ('reversible conduction failure') with a distal predominance Antibodies against ganglioside (mostly GA1) present in less than 50% of sera relevance not conclusive; tests for molecular mimicry negative Cao-Lormeau et al. Lancet 2016

16 Conclusions Some (but not all) forms of GBS have a definite pathogenic mechanism GBS can occur as epidemics (paralleling infectious outbreaks) In the setting of Zika virus infection The phenotypic presentation of GBS is quite homogeneous The overall prognosis is good (provided ICU is accessible for respiratory support) The mechanism of GBS remains poorly understood