Guillain-Barré Syndrome (GBS)

OVERVIEW

Guillain-Barré Syndrome (GBS) is the most common and most severe acute paralytic neuropathy, consisting of multiple variants with distinct clinical and pathological features

• two main pathological types:
  • acute motor axonal neuropathy
  • acute inflammatory demyelinating polyneuropathy
• can progress to  a chronic form
• affects about 1 in 100,000 people each year (higher rates in elderly than young)
• may be associated with infectious outbreaks (e.g. Campylobacter infection)

CAUSE

GBS is an autoimmune response to an immune activating event, such as:

• Campylobacter jejuni enteritis (25-50%)
• viral (e.g. CMV, EBV, hepatitis A-E viruses, HIV, influenza, arboviruses (e.g. Zika, Chikungunya))
• Mycoplasma infection
• vaccination (e.g. influenza, rabies)

PATHOPHYSIOLOGY

Precise interplay of host and infectious factors leading to autoreactivity remains uncertain

• immune activation event leads to autoantibody production
  • in the case of GBS-associated with Campylobacter jejuni  infection, auto-antibodies result from molecular mimicry (e.g. glycans expressed on bacterial lipooligosaccharides (LOS))
  • however, this occurs in <1% of people with the infection
  • other genetic and environmental factors are presumably important but poorly understood
• affects peripheral nerves, primarily spinal and cranial nerve roots
  • autonomic nerves sometimes effected
  • two major distinct pathologies of immune injury:
    • the myelin sheath and related Schwann-cell components are targeted in acute inflammatory demyelinating polyneuropathy
    • membranes on the nerve axon (the axolemma) are targeted in acute motor axonal neuropathy
• mainly a humorally-mediated, rather than T-cell-mediated disorder, at least in the progressive phase of nerve injury
• recovery involves dampening of the immune response and endogenous repair of nerves

The immune activating event affects the clinical phenotype and prognosis

• e.g. C jejuni infections are usually associated with a pure motor axonal form of GBS, more severe limb weakness, and a serological antibody response directed against GM1 and GD1a gangliosides

CLINICAL FEATURES

Course

• immune activation, usually due to infection (e.g. Campylobacter, viral or Mycoplasma)
  • preceding respiratory or gastrointestinal infection reported by 2/3 of patients
• progression
  • sensory and/or cranial nerve involvement over 1-2 weeks
  • peak clinical deficits at 2-4 weeks
    • usually 2 weeks
    • subacute GBS may progress up to 6 weeks
  • recovery period in survivors lasts months to years
• Severity and duration of disease is highly diverse
  • can range from mild weakness with spontaneous recovery to  quadriplegic and ventilator-dependence without signs of recovery for several months resulting in severe, permanent disability though all surviving patients will show some signs of improvement

Motor-sensory features

• bilateral, symmetrical limb weakness, typically ascending
  • may initially only affect lower limbs
  • usually starts distally, but can start more proximally
  • may have facial, oculomotor, or bulbar weakness, which might then extend to involve the limbs (Miller-Fisher syndrome)
• areflexia
  • may initially be normal or even hyperreflexic
• paraesthesia
  • sensory symptoms and signs are common
  • usually milder than motor
  • 15% of GBS patients have no sensory symptoms (pure motor)
• muscular or radicular pain
  • commonly back pain, but not always
  • may precede weakness in 1/3 cases

Other features

• autonomic dysfunction
  • diarrhoea, vomiting, dizziness, abdominal pain, ileus, orthostatic hypotension, urinary retention, bilateral tonic pupils, fluctuating heart rate and dysrhythmias, decreased sweating, salivation and lacrimation
• respiratory failure (affects 20-30% of cases)
• corneal ulceration (poor lid closure)

CLASSIFICATION

There are axonal and demyelinating forms:

1. sensory and motor
   • classic or AIDP or acute motor-sensory axonal neuropathy (AMSAM)
2. motor
   • acute motor demyelinating neuropathy (ADMN) or acute motor axonal neuropathy (AMAN)
3. sensory
   • acute sensory loss, areflexia but no motor involvement
4. Miller Fisher syndrome (~5%)
   • classic triad of ophthalmoplegia, ataxia and areflexia
   • may present as isolated oculomotor palsy
   • may progress to weakness of the limbs (Miller Fisher-Guillain-Barré overlap syndrome)
5. Bickerstaff’s brainstem encephalitis (BBE)
   • similar to the Miller Fisher variant but with altered level of consciousness and long tract signs
6. pharyngeal-cervical-brachial
   • arm weakness, dysphagia and facial weakness
7. pandysautonomia (rare form of GBS and characterised by pure autonomic involvement without motor weakness.)
   • diarrhoea, vomiting, dizziness, abdominal pain, ileus, orthostatic hypotension, urinary retention, bilateral tonic pupils, fluctuating heart rate  and dysrhythmias, decreased sweating, salivation and lacrimation

Of note:

• Classification is not always possible
• Acute pure sensory neuropathies are not currently part of the GBS diagnosis

INVESTIGATIONS

The diagnosis is largely based on clinical patterns

• diagnostic biomarkers are not available for most variants of the syndrome

CSF

• elevated protein (only after 5-7 days of disease)
  • sometimes termed ‘cytoalbuminological dissociation’: ncreased CSF protein in the absence of increased WBCs
  • absence does not rule out GBS or make the diagnosis less likely
• some patients may have oligoclonal banding
• 5% of GBS patients have a mild increase in CSF cell count (5–50 cells per μL)

Blood tests

• high IgG
• antiganglioside GM1 and GD1a antibodies (axonal forms)
• GQ1b antibodies (Miller Fisher variant)

Nerve conduction studies

• Use
  • helpful in clinical practice, but are generally not essential for the diagnosis of GBS
  • required for GBS classification (may need serial studies over weeks)
  • may have prognostic use (e.g. low compound motor action potentials (CMAPs) indicates more severe weakness)
  • at least four motor nerves, three sensory nerves, F-waves, and H-reflexex should be assessed
• Acute inflammatory demyelinating polyneuropathy
  • decreased motor nerve conduction velocity
  • prolonged distal motor latency
  • increased F-wave latency
  • multifocal conduction blocks
  • abnormal temporal dispersion of CMAPs
• Acute motor axonal neuropathy
  • no features of demyelination
    • decreased motor, sensory amplitudes, or both
    • one demyelinating feature in one nerve, if distal CMAP amplitude is less than 10% lower limit of normal, can be found
    • distal CMAP amplitude less than 80% lower limit of normal in at least two nerves
  • Transient motor nerve conduction block might be present
• Findings
  • Can be physiological normal in the tractable nerve(s) tested (especially early)
  • Abnormalities are most pronounced 2 weeks after start of weakness

MRI spine

• consider to exclude a high cervical lesion

Lung function tests

• If FVC <20 mL/kg transfer to ICU
• Intubate if FVC <15 mL/kg or negative inspiratory pressure < -25 cm H₂O

Screen for infection

• viral PCR/ antibodies
• stool culture for Campylobacter
• mycoplasma antibodies and CXR

DIFFERENTIAL DIAGNOSIS

Chronic inflammatory demyelinating polyneuropathy with acute onset

• accounts for about 5% of cases initially diagnosed as GBS
• suspect if:
  • three or more periods with clinical deterioration, or
  • new deterioration after 8 weeks from onset of weakness
• treated with chronic maintenance IV Ig therapy and/or corticosteroids

Features that raise doubt about the diagnosis of GBS, and make an alternate diagnosis more likely:

• CSF: increased number of mononuclear cells or polymorphonuclear cells (>50 cells per μL)
• Severe pulmonary dysfunction with little or no limb weakness at onset
• Severe sensory signs with little or no weakness at onset
• Bladder or bowel dysfunction at onset
• Fever at onset
• Sharp spinal cord sensory level
• Marked, persistent asymmetry of weakness
• Persistent bladder or bowel dysfunction
• Slow progression of weakness and without respiratory involvement (consider subacute inflammatory demyelinating polyneuropathy or acute onset chronic inflammatory demyelinating polyneuropathy)

See ICU-acquired weakness for Differential Diagnosis

MANAGEMENT

Resuscitation

• Life threats include:
  • airway obstruction (e.g. secretions, bulbar palsy)
  • respiratory failure (e.g. weakness) or complications (e.g. infection, aspiration)
  • autonomic disturbance (e.g. dysrhythmias, hypotension)
• Intubate if:
  • (1) VC falls < 15mL/kg (1000mL)
  • (2) when secretions become difficult to manage
  • (3) respiratory failure
  • (4) VC fall rapidly over 6 hours

• often will require a mandatory mode (can’t trigger because of weakness)
• don’t wean until VC > 15mL/kg
• often require < 4 weeks of ventilation
• many are intubated for < than 7-10 days
• tracheostomy
• slow respiratory wean

Specific therapy

• Immunotherapy, either plasma exchange or IV immunoglobulin are first line options:
  • plasma exchange
    • indication
      • within the first 4 (preferably 2) weeks from onset in GBS patients  who are unable to walk unaided (GBS disability score >2)
      • GBS patients who are still able to walk might improve more rapidly after 2 plasma exchange sessions
    • 5 plasma exchanges of 2-3 L (50mL/kg) over 2 weeks
    • use albumin as replacement fluid
  • IV Immunoglobulin (IV Ig)
    • indication
      • start within the first 2 weeks after onset of weakness in patients unable to walk unaided
    • 0.4 g/kg/day for 5 doses over 5 days
    • alternative is (2 g/kg body-weight) given in 2 days (1 g/kg per day) but may have more side-effects and children with this regimen have higher rates of treatment-related fluctuations (TRFs)
    • more convenient, less side-effects, but more expensive than plasma exchange
  • Treatment-related fluctuations (TRFs)
    • TRFs refer to deterioration after initial improvement or stabilisation
    • affects 10% patients  and usually occur within the first 8 weeks after start of treatment
    • Repeated treatment with IV Ig is indicated (2 g IV Ig/kg in 2–5 days)
  • Evidence
    • plasmapheresis and IV Ig have proven benefit for the indications listed in several RCTs
    • no evidence of additional benefit for both IV IgG and plasmapheresis as co-therapy
    • steroids are not effective (both oral steroids and IV methylprednisolone)
    • repeat treatment of TRfs with IV Ig is not proven by RCTs but supported by observational studies
    • Eculizumab is currently only an experimental therapy

Supportive care and monitoring

• Initially check for progression of the following regularly (e.g. q1-3h)
  • respiration
  • progressive weakness
  • swallowing difficulties
  • autonomic dysfunction
  • pain

• enteric feeding (fine bore NG tube)
• VTE prophylaxis
• early initiation of physiotherapy and rehabilitation
• psychosocial support
• analgesia
  • pain can be severe and prolonged
  • options, despite a lack of evidence, include
    • simple analgesia (e.g. paracetamol)
    • gabapentin
    • tricyclics antidepressants (e.g. amitriptyline)
    • anticonvulsants (e.g. carbamazepine, valproate)
    • ketamine

Seek and treat underlying cause and complications

• immune activating illness has usually resolved (e.g. Campylobacter enteritis)
• complications include:
  • venous thromboembolic disease
  • pressure injuries
  • respiratory tract infections

Disposition

• all GBS patients require meticulous monitoring and supportive care
• Those that develop respiratory failure and/or autonomic disturbance require ICU admission, as do most patients requiring immunotherapy

PROGNOSIS

The EGOS score (Erasmus GBS outcome scale) can be used 2 weeks after admission to predict the ability of the patient to walk at 6 months, and is based on:

• age > 40 years
• preceding Campylobacter infection or diarrhoeal illness (in the past 4 weeks)
• high disability at nadir

The mEGOS score (modified Erasmus GBS outcome scale) can be used at 1 week, and replaces disability with the Medical Research Council (MRC) Scale for Muscle Strength score.

Risk of respiratory failure can be predicted by the EGRIS score (Erasmus GBS Respiratory Insufficiency Score) based on:

• severity of weakness (expressed as MRC sum score)
• onset of weakness (i.e. rapid)
• facial palsy, bulbar weakness, or both

Peroneal nerve conduction block and low vital capacity are also predictive of respiratory failure, but not part of the EGRIS score

Mortality and morbidity

• 3-7% mortality from medical complications in hospital (Europe and North America)
• death is usually due to:
  • respiratory failure or complications
  • autonomic complications (e.g. dysrhythmia)
• Up to 20% of patients are still significantly disabled at 6 months
• 15% still have significant functional disability at 1 year, improvements can still occur after 3 or more years
• Most patients have residual pain and fatigue, due to persistent axonal loss
• Recurrence rate is 7% with the mean interval between recurrences being 7 years

Typical course in patients who recover

• to walking unassisted: 3 months
• full recovery: 6 months

However, there is permanent disability in severe cases

References and Links

• Eponymythology – Guillain–Barré syndrome
• Eponymythology – Jean-Baptiste Octave Landry (1826 – 1865)
• Eponymythology – Georges Charles Guillain (1876 – 1961)
• Eponymythology – Jean-Alexandre Barré (1880 – 1967)
• Eponymythology – André Strohl (1887 – 1977)
• Eponymythology – Charles Miller Fisher (1913 – 2012)

Journal articles

• Fokke C, van den Berg B, Drenthen J, et al. Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria. Brain. 2014; 137(Pt 1):33-43.[PMID 24163275]
• Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. The Cochrane database of systematic reviews. 2014; [PMID 25238327]
• Hughes RA, Swan AV, van Koningsveld R, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. The Cochrane database of systematic reviews. 2006; [PMID 16625544]
• Lehmann HC, Hartung HP, Hetzel GR, Stüve O, Kieseier BC. Plasma exchange in neuroimmunological disorders: part 2. Treatment of neuromuscular disorders. Archives of neurology. 2006; 63(8):1066-71. [PMID 16908731]
• Rajabally YA, Uncini A. Outcome and its predictors in Guillain-Barre syndrome. Journal of neurology, neurosurgery, and psychiatry. 2012; 83(7):711-8. [PMID 22566597]
• Raphaël JC, Chevret S, Hughes RA, et al. Plasma exchange for Guillain-Barré syndrome. The Cochrane database of systematic reviews. 2012; [PMID 22786475]
• Walgaard C, Lingsma HF, Ruts L, et al. Prediction of respiratory insufficiency in Guillain-Barré syndrome. Annals of neurology. 2010; 67(6):781-7.[PMID 20517939]
• Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome. Lancet. 2016; 388(10045):717-27. [PMID 26948435]
• Yuki N, Hartung HP. Guillain-Barré syndrome. The New England journal of medicine. 2012; 366(24):2294-304. [PMID 22694000]