LE SYNDROME DE GUILLAIN-BARRE

Transcription

1 FORMATION UNIVERSITAIRE SPECIFIQUE (FUS) Enseignement interuniversitaire MASTER DE SPECIALISATION EN MEDECINE INTERNE Samedi 19 dećembre 2015 Institute of Neurosciences LE SYNDROME DE GUILLAIN-BARRE Peter Van den Bergh, M.D., Ph.D. Professeur en Neurologie Centre de Référence Neuromusculaire

2 Guillain-Barré syndrome (GBS) Post-infectious rapidly progressive polyneuropathy Incidence 1.4/100,000 = 7000/yr in EU = 100,000/yr worldwide Life-time risk 1/1000 Any age but frequency increases with age Symmetric weakness of more than 1 limb Absent or reduced deep tendon reflexes Progression over maximum 4 weeks Diagnostic Criteria 2

3 Guillain-Barré syndrome (GBS) Mild sensory involvement 85% Cranial nerves in 60% Autonomic involvement in 15% Respiratory failure in up to 25% Pain and fatigue in most cases Ø Unability to walk at 6 months in 20% Ø Treatment-related fluctuations (TRF) in 10% Ø Progression to CIDP (Acute onset CIDP, A-CIDP) in 5% 3

4 onset weakness 1/3 pain before disease onset pain may persist for a long time and may be quite severe 4

5 Female, 48 y D0 paresthesias feet and hands, ascending D11 gait difficulty, dysphagia, tongue numbness, dyspnea D13 hospital admission cannot walk muscle weakness 4/5 arms, 3/5 legs absent DTRs stocking and glove hypoesthesia CSF protein 33 (D6) ENMG = demyelinating neuropathy (D15 and D30) no anti-gm1 antibodies 5

6 Female, 48 y D11-13 : nadir in 14 days Diagnosis: GBS Treatment: IVIG 2g/kg D15 19 D16-21: improvement and can walk again D22-28: worsening ++ with muscle weakness 3/5 and gait loss Treatment: IVIG 2g/kg D28 32 D49: slow improvement and transfer to rehab facility D60: discharge, moderate weakness, walks with crutch à GBS - Treatment-related fluctuation (TRF) 6

7 Guillain-Barré syndrome (GBS) Treatment-related fluctuation (TRF) Improvement after treatment followed by worsening within 2 months Stabilisation for > 1 week after treatment followed by worsening within 2 months Recurrent GBS Two or more episodes with an interval of 2 months (when fully recovered) or 4 months (when only partially recovered) 7

8 Caroline, August 2007 Paresthesias in hands, tongue and L side of upper lip Normal neurological and EMG examination 1 October 2007 Hospital admission because of gait difficulty and paresthesias in legs; horizontal diplopia DTR abolished in legs, normal sensation CSF protein 105 mg/dl EMG: demyelinating neuropathy 4-9 October 2007 Rapidly progressive ascending tetraparesis à IVIg 2g/kg

9 17-19 October 2007 Tetraplegia, respiratory failure, cardiovascular dysautonomia, ophthalmoplegia, mydriasis à mechanical ventilation No antiganglioside Abs (a.o. GQ1b) Mid-November 2007: Progressive motor recovery 08 December 2007: Extubation and transfer to rehab 25 December 2007: Almost complete recovery Mid-January 2008: Ascending paraparesis - dyspnea à IVIg 2g/kg 28 January 2008: Respiratory failure à transfer to ICU and mechanical ventilation February 2008: PE à no improvement à methylpdn 1mg/kg/d Mid-March 2008: Motor recovery - weaning from ventilator 08 May 2008: Discharge home Full recovery on methylpdn 8 mg/d à A-CIDP (acute onset-cidp)

10 Guillain-Barré syndrome (GBS) Treatment-related fluctuation (TRF) Improvement after treatment followed by worsening within 2 months Stabilisation for > 1 week after treatment followed by worsening within 2 months Recurrent GBS Two or more episodes with an interval of 2 months (when fully recovered) or 4 months (when only partially recovered) Progression > 2 months A-CIDP Mostly prominent sensory signs, Mostly no facial weakness, respiratory failure, autonomic involvement, preceding infection 10

11 Spectrum GBS AIDP AMAN AMSAN MFS variants EUR USA AIDP AMAN AMSAN MFS variants JAP CHINA Acute inflammatory demyelinating polyneuropathy (AIDP) Acute motor (and sensory) axonal neuropathy (AMAN or AMSAN) Miller Fisher syndrome (MFS) Variants (e.g., pharyngo-cervico-brachial, paraparetic)

12 Frequency of AMAN based on electrophysiological criteria (Ho et al., 1995; Hadden et al., 1998) Kuwabara and Yuki, 2013

13 AMAN AIDP Preceding infection C. jejuni CMV, EBV Epidemics Children (China, Mexico) No Cranial nerves Rare (< 20%) Frequent (60%) Sensory loss Usually none (< 10%) Frequent (70%) Pain Usually none Frequent (up to 66%) Autonomic involvement Rare More frequent Tendon reflexes Usually absent (preserved or exaggerated in 20%) Absent (preserved or exaggerated in 5%) Recovery 2 patterns (rapid and slow) Relatively uniform Kuwabara and Yuki, 2013

14 to help to support the clinical diagnosis to identify the subtype to exclude «mimic» disorders acute spinal cord disease myasthenia gravis periodic paralysis toxins (shellfish poisoning) tick paralysis poliomyelitis infections (Lyme) botulism GBS Electrophysiological studies acute intermittent porphyria critical illness neuropathy/myopathy

15 GBS Electrophysiological studies to help to support the clinical diagnosis to identify the subtype to exclude «mimic» disorders motor nerve conductions: recognition of primary demyelination à AIDP sensory nerve conductions: differentiate AMAN from AMSAN

16 GBS Electrophysiological Subtypes AIDP à multifocal process = some nerves / some nerve segments à wide range of degree of demyelination = intermediate conduction values à mild severe (inexcitable nerves) à timing of nerve conduction studies 50% + at 1 wk 85% + at 3 wks (Albers et al., 1985) 60% + at 1 wk 72% + at 4 wks (Meulstee et al., 1995)

17 Early electrophysiological diagnosis of GBS retrospective study of 58 patients examination within 7 days after onset Chanson and Eganiz-Laguna, 2014

18 GBS Electrophysiological Criteria Ho et al., 1995; Hadden et al., 1998 AIDP AMAN AMSAN CV < 90% in 2 nerves CB > 50% or unequivocal temporal dispersion in 2 nerves distal latency > 110% in 2 nerves min. F wave latency > 120% in 2 nerves no evidence of demyelination (as above) dcmap amplitude < 80% in 2 nerves as for AMAN + SNAP amplitude < 50% in 2 nerves

19 GBS Electrophysiological Subtypes AMAN: patterns of conduction abnormalities simple axonal degeneration transient conduction block / slowing (Kuwabara et al., 1998, Hiraga et al., 2005) Transient conduction block / slowing = Early-Reversible Conduction Failure Origin is non-demyelinating but axonal because of impaired conduction at node of Ranvier due to antiganglioside antibodies à nodopathy-paranodopathy (Uncini and Kuwabara, 2012) 19

20 Pathophysiology of AMAN Early-Reversible Conduction Block Binding of anti-ganglioside antibodies to the node/paranode Complement deposition : MAC (C5-b9) - Myelin detachment (leak of driving current) - Disruption of Na+ channel clusters Reduced safety factor Axonal degeneration Slow recovery Conduction block Rapid recovery 20 (Kuwabara and Yuki, 2013)

21 GBS Electrophysiological Subtypes AIDP AMAN Acute MCB neuropathy Early-Reversible Conduction Failure Yuki and Hartung, 2012 (Yuki & Hartung, 2012)

22 Uncini et al., 2010 Serial electrophysiological studies: 24% of patients changed classification, mostly to AMAN

23 AMAN is associated with antiganglioside IgG Ab (GM1, GM1b, GD1a, GalNac-GD1a) Sekiguchi et al., 2012

24 AIDP Electrophysiological Criteria Ho et al., 1995; Hadden et al., 1998 AIDP CV < 90% in 2 nerves CB > 50% or unequivocal temporal dispersion in 2 nerves distal latency > 110% in 2 nerves min. F wave latency > 120% in 2 nerves Van den Bergh and Piéret, 2004 AIDP CV < 70% in 2 nerves CB > 50% or abnormal temporal dispersion >30% in 2 nerves distal latency > 150% in 2 nerves absent F waves or min. latency > 120% in 2 nerves

25 GBS Electrophysiological Subtype Criteria Van den Bergh and Piéret, 2004 AIDP CV < 70% in 2 nerves CB > 50% or abnormal temporal dispersion >30% in 2 nerves distal latency > 150% in 2 nerves absent F waves or min. latency > 120% in 2 nerves Rajabally et al AMAN Distal CMAP < 80% in 2 nerves CB < 30% in 2 nerves F wave absence in 2 nerves F wave absence in 1 nerve with dcmap > 20% OR CB < 30% + dcmap < 80% in one other nerve)

26 GBS Electrophysiological Subtype Criteria < 21 d after symptom onset median = 9 d (IQR 6)

27 GBS Electrophysiological Subtype Criteria Serial studies may still be necessary (Uncini et al., 2014)

28 Pathophysiology of AMAN

29 Pathophysiology of AMAN Molecular mimicry Lipo-oligosaccharides Gangliosides Yuki & Kuwabara 2007

30 Brain 2010

31 Brain 2010 Complement inhibition (eculizumab) completely protects nodes of Ranvier against GD1a antibodymediated injury (nodal proteins and sodium current) Calpain inhibition preserves nodal protein and sodium channel integrity but not sodium currents à Membrane Attack Complex (MAC) pores are responsible for conduction loss

32 Pathophysiology of AMAN Kuwabara & Yuki 2013

33 Pathophysiology of AIDP Kuwabara & Yuki 2013

34 Pathophysiology of AIDP Separation node - juxtaparanode NF-155 > AIDP Contactin-1 > AIDP Nav clustering NF-186 > AMAN Gliomedin-1 > AIDP Ezrin-Radixin-Moesin = ERM complex Moesin > AIDP Membrane-organising extension spike protein

35 GBS prognosis Complete recovery 15% Pain and fatigue most cases Minor deficit 65% Unable to walk at 6 months 20% Death 3-8% (sepsis, ARDS, pulmonary embolism, cardiac arrest)

36 Progressive phase Plateau phase Herstelfase Recovery phase Late phase Normal GBS Mild = able to walk unaided Severe = unable to walk unaided Paralysis weeks months // // years Rate of progression, severity and speed of recovery are highly variable Courtesy P. Van Doorn

37 Disability in a cohort of Dutch patients with GBS (N=397, inclusion period ) GBS disability score : normal : minor deficits : unable to run : walk with assistance : wheelchair bound : artificial ventilation : dead Courtesy P. Van Doorn

38 GBS factors predicting poor prognosis Artificial ventilation Rapid progression Low GBS disability and MRC sum score Areflexia Low vital capacity Cranial nerve dysfunction Nerve conduction: demyelination Poor long-term prognosis Rapid progression Low GBS disability and MRC sum score Advanced age Diarrhoea / C. Jejuni EMG: axonal damage IgG1 anti-gm1 antibodies Anti-GQ1b antibodies / CMV

39 Prognostic models: Erasmus GBS Respiratory Insufficiency Score (EGRIS) Prediction of respiratory insufficiency in GBS (Walgaard et al., Ann Neurol 2010)

40 Prognostic models: Erasmus GBS Respiratory Insufficiency Score (EGRIS) Predicted probability respiratory insufficiency 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 1/ 34 2/ 97 7/ / / 72 25/ 42 15/ 22 5/ EGRIS 2 patients with similar MRC sumscore of 25 (3 points) Patient 1: - Weakness for 1 day (2 points) - Facial weakness (1 point) Total EGRIS = 6 Patient 2: - Weakness for 10 days (0 points) - No facial or bulbar weakness (0 points) Total EGRIS = 3

41 Prognostic models: modified Erasmus GBS outcome score (megos) megos Chance unable to walk 4 wks 3 mths 6 mths D0 4 wks 3 mths 6 mths D0 Walgaard et al. Neurol 2011 D7 D7

42 Prognostic models: modified Erasmus GBS outcome score (megos) megos Chance unable to walk 4 wks 3 mths 6 mths D0 4 wks 3 mths 6 mths D0 Walgaard et al. Neurol 2011 D7 D7

43 Prognostic models: modified Erasmus GBS outcome score (megos) megos Chance unable to walk 4 wks 3 mths 6 mths D0 4 wks 3 mths 6 mths D0 Walgaard et al. Neurol 2011 D7 D7

44 GBS Treatment Goals accelerate recovery decrease complication rate decrease longterm residual neurologic deficits à General supportive care à Immunotherapy

45 GBS Supportive treatment Vital capacity à intubation ml/kg (15-19 ml/kg if bulbar paralysis) Bronchial clearing and assisted coughing Pulmonary embolism prophylaxis Gastrointestinal bleeding prophylaxis Decubitus and thrombosis profylaxis Check for infections (pulmonary, urinary) Check for dysautonomia (cardiovascular, intestinal, urinary) Pain control

46 GBS Immunotherapy Randomised Controlled Trials 1985 GBS Study Group N = 245 PE vs supportive care 1987 French GBS SG N = 220 PE vs supportive care PE effective PE effective 1992 Dutch GBS SG N = 150 IVIG vs PE Equally effective 1997 PE/SandoGl Trial N = 383 IVIG vs PE vs both 2004 Dutch GBS SG N = 225 IVIG vs IVIG +MP Equally effective Equally effective

47 GBS Treatment Cochrane Reviews 2013 Intravenous immunoglobuin for Guillain-Barré syndrome Hughes RA, Swan AV, van Doorn PA Plasma exchange for Guillain-Barré syndrome Raphael JC, Chevret S, Hughes RA, Annane D Corticosteroids for Guillain-Barré syndrome Hughes RA, van Doorn PA IVIG and PE are effective: < 2 wks after onset, gait loss PE + IVIG is not superior Steroids alone are not effective IVIG is first choice treatment: easy to use, less side-effects, less complications Conclusions

48 GBS Immunotherapy When and how? Patients unable to walk - within 2 wks from onset: 0.4 g IVIG/kg for 5 days or 1g/kg for 2 days Patients unable to walk and progressing for 2-4 wks: PE effective; IVIG no data Patients mildly affected (walking) - within 2 wks from onset: PE 2x? Secondary deterioration (treatment-related fluctuations): Repeat treatment (no RCT results) Progression over > 2 months: most likely A-CIDP: treat as CIDP

49 GBS Treatment - Questions Does IVIG help in GBS > 2 weeks after onset? Is IVIG indicated in mild GBS? 5-14% of patients remain ambulant 38% of patients have problems with hand function or are unable to run at 3-6 months Is IVIG effective against fatigue? What is the optimal dosage and regimen of IVIG? Is 1 IVIG course sufficient in all patients? severely affected patients (see prognostic models) treatment-related fluctuations (TRFs) in 10%

50 GBS Treatment - Questions IVIG and prognosis in GBS? Acute onset CIDP A-CIDP? van Doorn 2010 & 2013

51 GBS Treatment New developments Second IVIG dosage in patients with poor prognosis effective in GBS patients with secondary progression of weakness after initial improvement (TRFs) possibly effective in a small uncontrolled series of severe unresponsive GBS patients (Farcas, Lancet 1997) patient with minor increase of serum IgG after standard dose IVIG have poorer prognosis (Kuitwaard, Ann Neurol 2009)

52 GBS Treatment - Questions Pharmacokinetics of IVIG in GBS 1 < < < > Kuitwaard et al. Ann Neurol 2009

53 GBS Treatment New developments Second IVIG dosage in patients with poor prognosis

54 GBS Treatment New developments prevents in ex vivo and in vivo GBS mouse model: complement activation and MAC deposition reduction of contractile strength prevents in in vivo GBS mouse model: loss of strength respiratory failure à Eculizumab may be an attractive treatment for GBS and other autoantibody-mediated neuropathies à RCT with Eculizumab is about to start