Institute of Neurosciences

FORMATION UNIVERSITAIRE SPECIFIQUE (FUS)

Enseignement interuniversitaire

MASTER DE SPECIALISATION EN MEDECINE INTERNE

Samedi 19 décembre 2015

LE SYNDROME DE GUILLAIN-BARRE

Peter Van den Bergh, M.D., Ph.D.

Professeur en Neurologie
Centre de Référence Neuromusculaire
 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 Diagnostic Criteria
• Progression over maximum 4 weeks

2
 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
 onset weakness

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

4
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
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
 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
 Caroline, 28.07.1980

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
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)

 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)

A-CIDP
• Progression > 2 months
• Mostly prominent sensory signs, Mostly no facial weakness,
respiratory failure, autonomic involvement, preceding infection
10
 Spectrum
GBS

AMAN EUR
AIDP MFS variants USA
AMSAN

AMAN
AIDP MFS variants JAP
AMSAN
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)
Frequency of AMAN based on electrophysiological criteria
(Ho et al., 1995; Hadden et al., 1998) Kuwabara and Yuki, 2013
 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 Absent (preserved or

or exaggerated in 20%) exaggerated in 5%)

Recovery 2 patterns (rapid and Relatively uniform

slow) Kuwabara and Yuki, 2013
 GBS
Electrophysiological studies
• 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
• acute intermittent porphyria
• critical illness neuropathy/myopathy
 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
 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)
Early electrophysiological diagnosis of GBS

• retrospective study of 58 patients

• examination within 7 days after onset
Chanson and Eganiz-Laguna, 2014
 GBS 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
AMAN • no evidence of demyelination (as above)
• dCMAP amplitude < 80% in 2 nerves
AMSAN • as for AMAN + SNAP amplitude < 50% in 2 nerves
 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 anti-
ganglioside antibodies à “nodopathy-paranodopathy”
(Uncini and Kuwabara, 2012)

19
 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 Conduction block

Slow recovery Rapid recovery

(Kuwabara and Yuki, 2013)

20
 GBS Electrophysiological Subtypes
AIDP AMAN Acute MCB neuropathy

Early-Reversible
Conduction Failure

(Yuki & Hartung, 2012)

Yuki and Hartung, 2012
 Uncini et al., 2010
Serial electrophysiological studies:
24% of patients changed classification, mostly to AMAN
AMAN is associated with antiganglioside IgG Ab
(GM1, GM1b, GD1a, GalNac-GD1a) Sekiguchi et al., 2012
 AIDP Electrophysiological Criteria
Ho et al., 1995; Hadden et al., 1998

• CV < 90% in 2 nerves

• CB > 50% or unequivocal temporal dispersion in 2 nerves
AIDP • distal latency > 110% in 2 nerves
• min. F wave latency > 120% in 2 nerves

Van den Bergh and Piéret, 2004

• CV < 70% in 2 nerves

• CB > 50% or abnormal temporal dispersion >30% in 2 nerves
AIDP
• distal latency > 150% in 2 nerves
• absent F waves or min. latency > 120% in 2 nerves
 GBS Electrophysiological Subtype Criteria
Van den Bergh and Piéret, 2004

• CV < 70% in 2 nerves

• CB > 50% or abnormal temporal dispersion >30% in 2 nerves
AIDP
• distal latency > 150% in 2 nerves
• absent F waves or min. latency > 120% in 2 nerves

Rajabally et al. 2014

• Distal CMAP < 80% in 2 nerves

• CB < 30% in 2 nerves
AMAN
• F wave absence in 2 nerves
• F wave absence in 1 nerve with dCMAP > 20% OR CB < 30%
+ dCMAP < 80% in one other nerve)
 GBS Electrophysiological Subtype Criteria

• < 21 d after symptom onset

• median = 9 d (IQR 6)
GBS Electrophysiological Subtype Criteria

Serial studies may still be necessary

(Uncini et al., 2014)
Pathophysiology of AMAN
 Pathophysiology of AMAN

Molecular mimicry
• Lipo-oligosaccharides
• Gangliosides

Yuki & Kuwabara

2007
Brain 2010
 Brain 2010

• Complement inhibition (eculizumab) completely

protects nodes of Ranvier against GD1a antibody-
mediated 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
Pathophysiology of AMAN

Kuwabara & Yuki

2013
Pathophysiology of AIDP

Kuwabara & Yuki

2013
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
 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)
 Progressive Plateau Recovery
Herstelfase Late
phase phase phase 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
Disability in a cohort of Dutch patients with GBS
(N=397, inclusion period 1987-2007)

GBS disability score

: normal
: minor deficits
: unable to run
: walk with assistance
: wheelchair bound
: artificial ventilation
: dead

Courtesy P. Van Doorn

 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
• Anti-GQ1b antibodies / CMV
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
Prognostic models: Erasmus GBS Respiratory
Insufficiency Score (EGRIS)

Prediction of respiratory insufficiency

in GBS (Walgaard et al., Ann Neurol 2010)
 Prognostic models: Erasmus GBS Respiratory
Insufficiency Score (EGRIS)
Score plot EGRIS
Predicted probability respiratory insufficiency

2 patients with similar MRC

100%
sumscore of 25 (3 points)
90%
80% Patient 1:
70% - Weakness for 1 day (2 points)
60%
- Facial weakness (1 point)

50% Total EGRIS = 6

40%
Patient 2:
30%
- Weakness for 10 days (0
20% points)
10% - No facial or bulbar weakness
0%
(0 points)
1/34 2/97 7/137 29/156 26/72 25/42 15/22 5/ 5
Total EGRIS = 3
0 1 2 3 4 5 6 7
EGRIS
Prognostic models: modified Erasmus GBS
outcome score (mEGOS)
Chance unable to walk
mEGOS 4 wks

3 mths
6 mths

D0

4 wks

3 mths

6 mths

D0 D7
Walgaard et al. Neurol 2011

D7
Prognostic models: modified Erasmus GBS
outcome score (mEGOS)
Chance unable to walk
mEGOS 4 wks

3 mths
6 mths

D0

4 wks

3 mths

6 mths

D0 D7
Walgaard et al. Neurol 2011

D7
Prognostic models: modified Erasmus GBS
outcome score (mEGOS)
Chance unable to walk
mEGOS 4 wks

3 mths
6 mths

D0

4 wks

3 mths

6 mths

D0 D7
Walgaard et al. Neurol 2011

D7
 GBS – Treatment

Goals
• accelerate recovery
• decrease complication rate
• decrease longterm residual neurologic deficits

à General supportive care

à Immunotherapy
 GBS – Supportive treatment

• Vital capacity à intubation

12-15 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
 GBS – Immunotherapy
Randomised Controlled Trials

1985 GBS Study Group N = 245 PE vs supportive PE effective

care
1987 French GBS SG N = 220 PE vs supportive PE effective
care
1992 Dutch GBS SG N = 150 IVIG vs PE Equally effective

1997 PE/SandoGl Trial N = 383 IVIG vs PE vs Equally effective

both
2004 Dutch GBS SG N = 225 IVIG vs Equally effective
IVIG +MP
 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

Conclusions
• 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
 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
 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%

•
GBS – Treatment - Questions
IVIG and prognosis in GBS

?
Acute onset CIDP
A-CIDP

van Doorn 2010 & 2013

 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)
•
GBS – Treatment - Questions
Pharmacokinetics of IVIG in GBS

1 < 3.99
2 < 7.30
3 < 10.92
4 > 10.92

Kuitwaard et al. Ann Neurol 2009

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