Management of

Guillain-Barre Syndrome

Peter Lin
R3 Neurology Resident

Guillain-Barre Syndrome
n

First described in 1916 by Guillain, Barre, and Strohl

Characterized by rapidly ascending paralysis,

hyporeflexia and CSF cytoalbuminologic dissociation

Pathology studies showed demyelination and

mononuclear infiltration in nerve roots

Thought to be acute demyelinating neuropathy

Clinical spectrum has expanded over last decade to

include a wide range of variants

Epidemiology
Most common cause of acquired generalized paralysis
n 1-4 per 100,000 per year
n All ages are affected
n Slight male preponderance
n Mean age of occurrence 40
n Mortality fallen from 33% to < 5% with ICU care
n Most common causes of death are ARDS, sepsis,
dysautonomia
n Presentations vary depending on country
n

Triggers
n

60-70% of cases preceded by a trigger infection such as

gastroenteritis or URI

Trigger event precedes symptoms by 1-3 weeks

Typically, viral upper respiratory infections

Certain pathogens predominate as triggers

n
n
n
n

C. jejuni
CMV
EBV
Mycoplasma

Other associated triggers

n

Vaccinations

Surgery

Cancer (Hodgkins disease)

Pregnancy

1/3 of patients have no preceding illness

Pathogenesis
n

Initially thought to be caused by an immune attack on

myelin

Peripheral nerve histology shows endoneurial

perivascular monocyte infiltration and multifocal
demyelination

Nerves may be affected at all levels from roots to distal

nerve endings (polyradiculoneuropathy)

A similar disease can be induced in animals by

immunization with nerve preparations enriched in
myelin (Experimental autoimmune neuritis)

Immune injury in AIDP

Bosch and Smith, from NICP, 3rd edition

Pathogenesis
n

Immune theories
n
n
n

Molecular mimicry of microbial structures and gangliosides

Humoral factors (antibodies to gangliosides)
Cell-mediated responses (Macrophage activation)

Further characterizations of variants showed that there

are demyelinating and axonal variants of GBS

Result from immune-mediated processes directed

against different antigens

A large number of reports have reported antibodies to

glycolipids, including GM1, GQ1b, various other
gangliosides, all components of the axonal membrane

Clinical presentation
n
n

Paresthesias and pain usually are first symptoms

Pain
n
n

Weakness
n
n
n
n

Usually a deep aching pain in lower back, may radiate to

buttocks, thighs, calves
May complain of burning, tingling, shock-like sensations
Follows sensory symptoms, beginning typically in legs and
ascending to arms
10% begin with arm weakness
Rarely weakness begins in face (cervical-pharyngeal-brachial)
Facial weakness occurs in at least 50% of patients and is usually
bilateral

Reflexes
n

Absent or depressed in virtually all cases

Clinical findings
n

Eye movement abnormalities

n
n

Sensory loss
n
n
n

Oculomotor paresis in 15% of patients

Ptosis and pupillary abnormalities can be seen
Variable
May be minimal or have severe kinesthetic loss
Panmodality sensory loss in stocking-glove is typical

Autonomic dysfunction
n
n
n
n
n
n

More frequent in severely affected patients

65% of patients had dysautonomia in some studies
Blood pressure lability
Cardiac arrhythmias
Urinary retention
Constipation

Clinical course
n
n

n
n

Disease progresses for days to 4 weeks

Typical course (90% of patients) is steady progression to
nadir within 3 weeks from onset of paresthesias
Plateau phase ranges from days to 6 months
Occasional patients will have stuttering or stepwise
course
Comprises variants which have unifying features of
clinical time course, CSF and electrodiagnostic findings,
and antecedent triggers

Clinical-pathologic spectrum
n

Acute inflammatory demyelinating

polyradiculoneuropathy (AIDP)

Axonal variants
n
n

Acute Motor Axonal Neuropathy (AMAN)

Acute Motor Sensory Axonal Neuropathy (AMSAN)

Without predominant weakness

n
n
n

Acute pandysautonomia
Pure sensory neuropathy
Miller-Fisher syndrome

Guillain-Barre Mimics
n
n
n
n
n
n
n

Transverse myelitis
Myasthenia Gravis
Vasculitic neuropathy
Porphyric neuropathy
Toxic neuropathies (thallium, arsenic, hexane)
Tick paralysis
Inflammatory meningoradiculopathies (Lymes,
CMV, HIV)

Lumbar puncture
n

CSF
n
n

n
n
n
n
n

Classically, albuminocytologic dissociation

90% of patients demonstrate protein elevation
without leukocytosis at time of maximal weakness
Normal cell counts and increased protein
5% of patients have pleocytosis of 10-20 cells
Abnormal findings level off after 1 month
Pleocytosis > 20 associated with HIV, Lymes
May be normal early on < 7 days, or in GBS variants

Serum Tests
n

Usually not helpful

LFTs may be abnormal in coexisting hepatitis

CK may be elevated in patients with severe pain

Hyponatremia may occur due to SIADH

Antibodies
n
n
n
n
n
n
n

Measurement of antibodies is not common practice

May have implications for prognosis
GM1 is associated with a severe pure motor variant
GM1b associated with C. jejuni - severe progression
GQ1b - Miller Fisher Variant
Does not change therapeutic approach
Correlation of antibodies with variants and clinical
courses is ongoing

MRI
n
n
n
n
n

MRI of brain is normal

Cranial nerve enhancement with gad has been
seen
Enhancement of spinal roots, conus, cauda
equina has been reported in severe cases
Findings are nonspecific and are not helpful in
confirming diagnosis
Rare patients with predominantly lower limb
involvement may benefit to rule out
compressive cord lesion

Electrodiagnosis
n
n

Most sensitive test in evaluating GBS

Patterns:
n Motor conduction block
n Prolonged distal latencies
n Temporal dispersion
n Slowing of nerve conduction
n Increased F-wave latency
n Operator-dependent
n Depends on variant (demyelinating vs. axonal)
n Normal NCV after several days of symptoms in
setting of severe weakness makes diagnosis unlikely

Goals of Treatment
n

To reduce the inflammatory attack early

n

Immunomodulation

Reduce morbidity
Disease related
n Secondary complications
n

Improve final outcome

Treatment Options
n

Plasmapheresis

IVIg

CSF Filtration

Steroids

Clinical Trials
n
n

Most trials examined those unable to ambulate

unaided or with respiratory progression
Endpoints
n
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Time to onset of motor recovery

Duration of time for mechanical ventilation
Hughes Disability Scale at 1 month, 6 months, 1 year
n
n
n

0 = normal to 6 = deceased with 3 = able to walk 5 meters

with walker or support
Many studies randomized only patients unable to walk
independently Hughes > 3 referred to as moderate
Mean improvement at 4 weeks was main primary outcome
measure for most major trials

Plasma Exchange Trials

n
n
n

Evidence suggesting that circulating humoral factors

induced demyelination led to study of plasmapheresis
The first treatment shown to be beneficial
North American (Guillain-Barre Study Group, Neurology,
1985)
n
n

245 patients treated within first 2 weeks with severe

Findings
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Improvement in function at 4 weeks

Decreased time to improve one clinical grade
Decreased time to independent walking (53 vs. 85 days)
Improved outcome at 6 months
Decreased number of days on ventilator (24 vs. 48 days)

Plasma Exchange Trials

n

French Cooperative Group (Ann Neurol, 1987)

n
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220 patients
Findings:
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Second French study 1997

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Decreased number of days to walk with assistance

71% full recover at 1 year follow-up vs. 52% supportive
556 patients
Studied PE in mild patients (able to walk but not run)
Concluded that mild patients benefited from 2 exchanges
Moderate and severe benefited from 4 but not 6

In the 1980s PE was the treatment of choice

Plasma Exchange Protocol

n

Standard regimen is 5 exchanges (totalling 200-250

mL/kg) on alternate days

Preferred replacement fluid is 5% albumin

Need to monitor BP, fibrinogen, PT, PTT

Contraindications:
n

septic shock, recent MI, marked dysautonomia and active

bleeding

Side effects
n
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Vasovagal reactions, hypovolemia, hemolysis from tube kinking,

air embolization, hematomas
Anaphylactoid reactions, hypocalcemia, thrombocytopenia,
hypothermia, hypokalemia, depletion of coagulation factors

Plasma Exchange: Consensus

n
n
n

Optimum number of exchanges is unknown

Volume of plasma removed is not known
Cochrane Database Meta-analysis 2002
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n

Six eligible trials with 649 patients

Conclusions
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Plasmapheresis is only proven treatment and should be

compared to as gold standard
In mild GBS, 2 exchanges are superior to none
In moderate GBS, 4 exchanges are superior to 2
In severe GBS, 6 are no better than 4
More beneficial when started within 7 days of onset
Is still beneficial in patients treated up to 30 days after

IVIg
n

Prepared from pooled plasma from donors

Contains entire array of variable region of antibodies in

normal serum

Complex mode of action

n
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Modulation of function of Fc receptors

Interference with activation of complement
Providing antiidiotypic antibodies
Modulation of functions of T and B cells

IVIg Trials
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Dutch trial 1992 (van der Meche, NEJM, 1992)

150 GBS patients unable to walk independently
randomized to IVIg vs. PE within 2 weeks of onset
At 4 weeks more patients showed improvement with
IVIg (53% vs. 34%)
Median time to improve one grade on Hughes scale was
less in IVIg group (27 days) vs. PE (41 days)
Criticisms
n
n
n

Plasma exchange group did not do as well as in North American

trial
Mean duration of disease prior to entry different (6 days vs. 11)
Relapse rate in IVIg treated patients was higher

Plasmapheresis vs. IVIg

n

Plasma Exchange/Sandoglobulin GBS Trial Group

(Lancet, 1997)
n
n
n

Compared PE with IVIg and PE/IVIg 383 patients

No significant difference between treatments at 4 weeks from
randomisation on Hughes scale
No difference in secondary measures including time to recover
unaided walking, time to d/c vent, recovery from disability at 48
weeks
No difference in the incidence of relapse after treatment

Conclusions:
n
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PE and IVIg have equivalent efficacy

No benefit from combined treatments over individual
Equivalent risk of relapse

IVIg Protocol
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Costs less and is easier to use

No need for central access
Standard dose is 0.4 g/kg for 5 days
Half-life is 3 to 6 weeks
Adverse effects include aseptic meningitis, acute
renal failure, ischemic stroke, anaphylactic shock
Need to monitor creatinine levels
No data on mild patients (ambulatory)

Preferred Treatment
n

Choice of IVIg or PE is a matter of convenience

and practicality
IVIg preferred in rural areas, hospitals where PE
not available, and in patients with
contraindications to PE
In all other cases, data support no superiority of
one over other
No clear data on efficacy of treatments in GBS
variants, mild disease (ambulatory)

Progression with treatment

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18% of patients will continue to deteriorate after

receiving full course of IVIg or plasmapheresis
10% of patients will improve and then deteriorate
(relapse)
Associated medical conditions appear to correlate best
with increased risks of relapse, whereas earlier treatment
onset is associated with decreased relapse
Anecdotal evidence for second course of same therapy
showing benefit
Unclear whether improvement secondary to therapy
versus natural history of disease
Controlled trials are in the planning phase

CSF Filtration
n

n
n

n
n

Soluble pathogenetic factors can be removed

from site where nerve conduction impeded or
nerve damage inflicted
30 to 50 mL of CSF filtered and reinfused
No difference in outcome vs. plasma exchange
in one small study (Wollinsky, Neurology, 2001)
Underpowered to establish equivalence
Experimental only at this time

Steroids
n
n

Corticosteroids alone are of no benefit

GBS Steroid Trial Group, Lancet, 1993
n
n
n

n
n

242 patients on Solumedrol 500 mg for 5 days

Ineffective in altering natural history of GBS
May increase rate of relapse

Ongoing multicenter trial is taking place to see benefit of

IV steroids and IVIg simultaneously
Pilot observations suggested beneficial interaction
Steroids are of benefit in management of CIDP

ICU Admission
n
n

n
n
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Patients with rapid progression (< 7 days)

Neck weakness with inability to raise
head against gravity
Bulbar dysfunction
Bilateral facial weakness
Significant dysautonomia
Aspiration

ICU Management
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Respiratory support
Fluids
Bowel/bladder care
Autonomic dysfunction
Skin, eye, mouth care
Pain management
Nutrition
DVT prophylaxis
Psychologic support

Respiratory Failure
n

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Respiratory failure usually occurs within 1 week after

onset of paresthesias
1/3 of patients will eventually require ventilator
Unusual for diaphragmatic failure to develop > 2 weeks
into illness
Evident by interrupted speech, inability to count to 20
May be accompanied by tachycardia and sweating
Rapid decline may occur unexpectedly
Serial measurements are helpful in anticipating
mechanical ventilation

Respiratory Management
n
n
n

At risk for atelectasis due to diaphragmatic

akinesis
Chest PT and frequent oral suctioning in those
with impaired cough
Respiratory measurements
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FVC
MIF

Lung expansion techniques

n
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Incentive spirometry
Maximal inspiration with cough maneuvers

Decision to intubate
n
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Vital capacity less than 15 mL/kg

PaO2 < 70
Inability to protect airway
20-30-40 rule (Lawn et al., Arch Neurol 2001)
n Vital capacity < 20 mL/kg
n MIF < 30 cm H2O
n Max exp. Pressure < 40 cm H2O
n Change from > 30% from baseline

Weaning
n

n
n

Preferred approach is to reduce IMV rate with

maximum pressure-support
Start once vital cap 15 mL/kg and tidal volumes of 1012 mL/kg
Pressure support is reduced to 5 cm H2O
Diaphragm weakness improves even before
improvement in limbs
Should not attempt weaning when dysautonomia is
still present
Weaning should be expected in 20 to 30 days

Fluids
n
n

Isotonic saline infusion 2 liters daily

Should be adjusted once enteric feeding
started
Larger volumes needed in those on
ventilators and with fevers

Bowel/bladder Issues
n

Constipation
Slowing of bowel activity due to bedrest
n Stool softeners
n Adynamic ileus may occur but rare
n

Bladder paralysis
n

Indwelling catheter

Dysautonomia
n
n
n
n
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Autonomic storms occur commonly in rapidly

progressive GBS but may be present with mild weakness
Common manifestations are spontaneous BP changes
and cardiac arrhythmias
Wide fluctuations over minutes
Due to impaired baroreceptor buffering
Spontaneous fluctuations in blood pressure should be
left alone
Antihypertensive and pressors should be used with
caution
Persistent hypotension can be treated with
Trendelenburg positioning and albumin infusion

Arrhythmias
n

Sinus bradycardia and tachycardia

Can have sinus arrest and AV block

Tracheal suctioning may provoke

Complete heart block may occur

Pain management
n
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n

Hot packs
Oral or parenteral opioids
NSAIDs for back and radicular pain
Epidural morphine
Recovery phase neuropathic pain
responds to Elavil or Mexiletine

General care
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Skin should be kept dry

Eyedrops for those who cannot close eyes
completely
May need taping of eyelids at night
Mouth care including toothbrushing and
inspection for candidiasis
Regular turning, positioning and padding
Splints, foot boards to prevent contractures
Early physical therapy to maintain ROM

Nutrition
n

Enteral nutrition should be started in those with

diminished swallowing mechanics, intubated

Contraindicated in adynamic ileus

Ileus occurs in minority of patients

Should be treated with suctioning, IV

administration, placement of flatus tube

Other care issues

n

Psychologic support
Frequent discussion with patient
n Clear projection of future course
n

Stress ulcers
n

Proton pump inhibitors for ventilated patients

DVT prophylaxis
Many patients cannot tolerate SCDs/TEDS
n Subcutaneous Heparin
n

Outcome
n
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GBS is monophasic in majority of patients

Recurrence very unusual, but have been known
to occur after long asymptomatic interval (up to
36 years)
Predictors of poor outcome:
n
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n

C. jejuni infection, antecedent diarrheal illness

Old age
Comorbid lung disease
Degree of axonal degeneration on EMG/NCV
Prolonged ventilatory support
Rapidly progressive weakness prior to presentation < 7 days

Recovery
n

80% of patients recover within 6 months

n
n

n
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15% recover completely

65% recover with minor deficits that do not interfere
with ADLs
5-10% have persistent motor weakness
3-5% die despite intensive care

In patients with persistent motor weakness ,

improvement can continue up to 2 years