Guillain-Barr Syndrome

Article Last Updated: Dec 19, 2007

Background

In 1859, Landry published a report on 10 patients with an ascending paralysis. 1 This was
followed by a report in 1916 written by 3 French physicians working in the Sixth Army
camp during the First World War; they described 2 French soldiers with motor weakness,
areflexia, and albuminocytological dissociation in the cerebrospinal fluid.2 In this report
Guillain, Barr, and Strohl carefully recorded and interpreted the tendon reflexes of their
patients and recognized the peripheral nature of the illness. The identified syndrome was
later named Guillain-Barr syndrome (GBS). Historically, GBS was a single disorder;
however, current practice acknowledges several variant forms.

GBS is a heterogeneous grouping of immune-mediated processes generally characterized

by motor, sensory, and autonomic dysfunction. In its classic form, GBS is an acute
inflammatory demyelinating polyneuropathy characterized by progressive symmetric
ascending muscle weakness, paralysis, and hyporeflexia with or without sensory or
autonomic symptoms; however, variants involving the cranial nerves or pure motor
involvement are not uncommon. In severe cases, muscle weakness may lead to
respiratory failure, and labile autonomic dysfunction may complicate the use of
vasoactive and sedative drugs.

Pathophysiology

Although the clinical syndrome classically presents as a rapidly progressive acute

polyneuropathy, several pathologic and etiologic subtypes exist. Most patients with GBS
exhibit absent or profoundly delayed conduction in action nerve fibers. This aberrant
conduction results from axon demyelination occurring primarily in peripheral nerves and
spinal roots, but cranial nerves may be involved as well.

GBS is believed to result from autoimmune humoral- and cell-mediated responses to a

recent infection or any of a long list of medical problems. Its relation to antecedent
infections and the identification of various antiganglioside antibodies suggest that
molecular mimicry may serve as a possible mechanism. 3, 4 Antibodies formed against
ganglioside-like epitopes in the lipopolysaccharide (LPS) layer of some infectious agents
have been shown in both necropsy and animal models to cross-react with the ganglioside
surface molecules of peripheral nerves.3 Symptoms generally coincide pathologically
with various patterns of lymphocytic infiltration and macrophage-mediated
demyelination, depending on the subtype in question. Recovery is typically associated
with remyelination. In a subset of patients, GBS is associated primarily with myelin-
sparing axonal damage resulting from a direct cellular immune attack on the axon itself.

The acute inflammatory demyelinating polyneuropathy (AIDP) subtype is the most

commonly identified form in the United States. It is generally preceded by an antecedent
bacterial or viral infection. Nearly 40% of patients are seropositive for Campylobacter

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jejuni. Lymphocytic infiltration and macrophage-mediated demyelination of peripheral
nerves is present. Symptoms generally resolve with remyelination.

The acute motor axonal neuropathy (AMAN) subtype is a purely motor subtype that is
more prevalent amongst pediatric age groups. Nearly 70-75% of patients are seropositive
for Campylobacter. One third of these cases may actually be hyperreflexic. The
hyperreflexia mechanism associated with AMAN is not known, but dysfunction of the
inhibitory system via spinal interneurons may increase motor neuron excitability.
Hyperreflexia is significantly associated with the presence of anti-GM1 antibodies. 1
Inflammation of the spinal anterior roots may lead to disruption of the blood-CNS
barrier.3 AMAN is generally characterized by a rapidly progressive weakness, ensuing
respiratory failure, and good recovery.

Acute motor-sensory axonal neuropathy (AMSAN) is an acute severe illness differing

from AMAN in that AMSAN also affects sensory nerves and roots. 5 Patients are typically
adults with both motor and sensory dysfunction, marked muscle wasting, and poor
recovery.

Miller-Fisher syndrome (MFS) is a rare variant that typically presents with the classic
triad of ataxia, areflexia, and ophthalmoplegia. Acute onset of external ophthalmoplegia
is a cardinal MFS feature.3 The ataxia tends to be out of proportion to the degree of
sensory loss. Patients may also have mild limb weakness, ptosis, facial palsy, or bulbar
palsy. Anti-GQ1b antibodies are prominent in this variant, and patients have reduced or
absent sensory nerve action potentials and absent tibial H reflex. 6 Patients with acute
oropharyngeal palsy carry anti-GQ1b/GT1a IgG antibodies. 3 Recovery generally occurs
within 1-3 months.

Acute panautonomic neuropathy is the rarest of all variants and involves both the
sympathetic and parasympathetic nervous systems. Cardiovascular involvement is
common, and dysrhythmias are a significant source of mortality in this form of the
disease. The patient may also experience sensory symptoms. Recovery is gradual and
often incomplete.

Frequency

United States

The incidence is 1-3 per 100,000 inhabitants, making GBS the most common cause of
acute flaccid paralysis in the United States.1, 2, 7

International

AMAN and AMSAN occur mainly in northern China, Japan, and Mexico, and they
comprise 5-10% percent of GBS cases in the United States.8

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AIDP accounts for up to 90% of cases in Europe, North America, and the developed
world.

Epidemiologic studies from Japan indicate that, in this region, a greater percentage of
GBS cases are associated with antecedent C jejuni infections and a lesser number are
related to antecedent cytomegalovirus infections compared with that in North America
and Europe.

Mortality/Morbidity

Most patients (up to 85%) with GBS achieve a full and functional recovery within 6-12
months. Recovery is maximal by 18 months past onset.9

Patients may have persistent weakness, areflexia, imbalance, or sensory loss.

Approximately 7-15% of patients have permanent neurologic sequelae including
bilateral footdrop, intrinsic hand muscle wasting, sensory ataxia, and dysesthesia.
The mortality rate varies but may be less than 5% in tertiary care centers with a
team of medical professionals who are familiar with GBS management. Causes of
death include adult respiratory distress syndrome, sepsis, pneumonia, pulmonary
emboli, and cardiac arrest.
Despite intensive care, 3-8% of patients die.
GBS can rarely be a recurrent disorder.10

Race

No racial preponderance exists.

Sex

The male-to-female ratio is 1.5:1. A Swedish epidemiologic study indicated that the
incidence of GBS is lower during pregnancy and increases in the months immediately
following delivery.11

Age

GBS occurs at all ages, but a bimodal distribution with peaks in young adulthood (15-35
y) and in elderly persons (50-75 y) appears to exist. Rare cases have been noted in
infants.12

History

The typical patient with GBS (likely AIDP) presents 2-4 weeks after a relatively benign
respiratory or gastrointestinal illness complaining of dysesthesias of the fingers and lower
extremity proximal muscle weakness. The weakness may progress over hours to days to
involve the arms, truncal muscles, cranial nerves, and muscles of respiration. The illness
progresses from days to weeks, with the mean time to the nadir of clinical function being

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12 days and 98% of patients reaching a nadir by 4 weeks. A plateau phase of persistent,
unchanging symptoms then ensues followed days later by gradual symptom
improvement. The mean time to improvement and clinical recovery are 28 and 200 days,
respectively.

Up to one third of patients require mechanical ventilation during the course of

their illness. Causes for this include cranial nerve involvement affecting airway
maintenance and respiratory muscle paralysis.
Motor dysfunction

o Symmetric limb weakness typically begins as proximal lower extremity
weakness and ascends to involve the upper extremities, truncal muscles,
and head.
o Inability to stand or walk despite reasonable strength, especially when
ophthalmoparesis or impaired proprioception is present.
o Respiratory muscle weakness with shortness of breath may be present.
o Cranial nerve palsies (III-VII, IX-XII) may be present. Patients may
present with facial weakness mimicking Bell palsy, dysphagia, dysarthria,
ophthalmoplegia, and pupillary disturbances. The Miller-Fisher variant is
unique in that this subtype begins with cranial nerve deficits.
o Lack of deep tendon reflexes is a hallmark sign.
Sensory dysfunction

o Paresthesia generally begins in the toes and fingertips and progresses
upward but generally not extending beyond the wrists or ankles.
o Pain is most severe in the shoulder girdle, back, buttocks, and thighs and
may occur with even the slightest movements.
o Loss of vibration, proprioception, touch, and pain distally may be present.
Autonomic dysfunction

o Cardiovascular signs may include tachycardia, bradycardia, dysrhythmias,
wide fluctuations in blood pressure, and postural hypotension.
o Urinary retention due to urinary sphincter disturbances may be noted.
o Constipation due to bowel paresis and gastric dysmotility may be present.
o Facial flushing and venous pooling secondary to abnormal vasomotor tone
may be present.
o Hypersalivation
o Anhydrosis
o Tonic pupils
Papilledema secondary to elevated intracranial pressure is present in rare cases.

Physical
Vital signs

o Patients may have tachycardia or bradycardia, hypertension or
hypotension, or hyperthermia or hypothermia.

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 o Low oxygen saturation may be present with advanced respiratory muscle
involvement.
Cranial nerves: Patients may present with facial weakness mimicking Bell palsy,
dysphagia, dysarthria, ophthalmoplegia, and pupillary disturbances.
Dysreflexia

o Patients with manifest weakness are invariably hyporeflexic or areflexic in
the involved areas.
o Respiratory symptoms
o Poor inspiratory effort or diminished breath sounds
Motor

o Symmetric limb weakness typically begins as proximal lower extremity
weakness and ascends to involve the upper extremities, truncal muscles,
and head.
o Inability to stand or walk despite reasonable strength, especially when
ophthalmoparesis or impaired proprioception is present.
o Hypotonia
o Wasting of limb muscles is not an acute finding.
Abdominal

o Paucity or absence of bowel sounds suggests paralytic ileus.
o Suprapubic tenderness or fullness may be suggestive of urinary retention.
Sensory: Patients may experience numbness, paresthesias, impaired
proprioception, and pain.
Papilledema secondary to elevated intracranial pressure is present in rare cases.

Causes

GBS has been associated with antecedent bacterial and viral infections, administration of
certain vaccinations, and other systemic illnesses. Case reports exist regarding numerous
medications and procedures; however, whether any causal link exists is unclear.

Bacterial infections include C jejuni, Haemophilus influenzae, Mycoplasma

pneumoniae, and Borrelia burgdorferi.1, 7
Viral infections include cytomegalovirus, Ebstein-Barr virus, and during
seroconversion with the human immunodeficiency virus (HIV).1, 7
Vaccines

o A study reviewing the cases of GBS during the 1992-1993 and 1993-1994
influenza seasons found an adjusted relative risk of 1.7 cases per 1 million
influenza vaccinations.13
o Epidemiologic studies from Finland and southern California failed to
validate an earlier retrospective study from Finland suggesting a cause-
effect relationship between oral polio vaccination and GBS,14, 15 while a

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 Brazilian study suggested that, based on a temporal association between
the vaccine and the onset of GBS, the vaccine may rarely trigger GBS.16
o Data from a large-scale epidemiologic study found that fewer cases of
GBS occurred following administration of tetanus toxoid containing
vaccinations than occurred in the baseline population.17
o An epidemiologic study failed to show any conclusive epidemiologic
association between GBS and the hepatitis B vaccine.18
o A large Latin American study of more than 2000 children with GBS
following a mass measles vaccination program in 1992 and 1993 failed to
establish a statistically significant causal relationship between
administration of the measles vaccine and GBS.19
o A recent report from the Centers for Disease Control and Prevention
(CDC) suggests that an increased incidence of GBS may exist amongst
recipients of the Menactra meningococcal conjugate vaccine.20
o Case reports exist regarding group A streptococci vaccines, the rabies
vaccine, and the swine flu vaccine; however, conclusive statistically
significant evidence is lacking.
Medications21

o A case-controlled study showed that patients with GBS had used
antimotility drugs and penicillins more often and oral contraceptives less
often. No definite cause-effect relationship has been established.
o Case reports exist regarding streptokinase, isotretinoin, danazol, captopril,
gold, heroin, and epidural anesthesia among others.
o Case reports cite associations between bariatric and other gastric
surgeries.22
Anecdotal associations include systemic lupus erythematosus, sarcoidosis,
lymphoma, surgery, renal transplantation, and snake bite.

Lab Studies
Diagnosis usually is made on clinical grounds. Laboratory studies are useful to
rule out other diagnoses and to better assess functional status and prognosis.
Lumbar puncture and spinal fluid analysis

o Elevated or rising protein levels on serial lumbar punctures and 10 or
fewer mononuclear cells/mm3 strongly support the diagnosis.
o Most, but not all, patients have an elevated CSF protein level (>400
mg/L), with normal CSF cell counts.
o Normal CSF protein level does not rule out GBS as the level may remain
normal in 10% of patients, and a rise in the CSF protein level may not be
observed until 1-2 weeks after the onset of weakness.
o CSF pleocytosis is well recognized in HIV-associated GBS.
Biochemical screening

o Biochemical screening includes electrolyte levels; liver function tests
(LFTs); CPK level; erythrocyte sedimentation rate (ESR); antiganglioside

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 antibodies; and antibodies to C jejuni, cytomegalovirus, Ebstein-Barr
virus, herpes simplex virus (HSV), HIV, and M pneumoniae.
o Syndrome of inappropriate antidiuretic hormone (SIADH) occurs in some
patients with GBS.
o LFT results are elevated in up to one third of patients.
o CPK and ESR may be elevated with myopathies or systemic inflammatory
conditions.
o Patients with the Miller-Fisher variant may have anti-GQ1b antibodies.
o Patients who have antibody subtype GM1 may have worse prognoses.
Stool culture for C jejuni
Pregnancy test

Imaging Studies
MRI

o MRI is a sensitive but nonspecific test.
o Spinal nerve root enhancement with gadolinium is a nonspecific feature
seen in inflammatory conditions and is caused by disruption of the blood-
nerve barrier.
o Selective anterior nerve root enhancement appears to be strongly
suggestive of GBS.
o The cauda equine nerve roots are enhanced in 83% of patients.

Other Tests
Forced vital capacity23

o Forced vital capacity (FVC) is very helpful in guiding disposition and
therapy.
o Patients with an FVC less than 15-20 mL/kg, maximum inspiratory
pressure less than 30 cm H2O, or a maximum expiratory pressure less than
40 cm H2O generally progress to require prophylactic intubation and
mechanical ventilation.
Nerve conduction studies2

o A delay in F waves is present, implying nerve root demyelination.
o Nerve motor action potentials may be decreased. This is technically
difficult to determine until the abnormality is severe.
o Compound muscle action potential (CMAP) amplitude may be decreased.
o Frequently, patients show evidence of conduction block or dispersion of
responses at sites of natural nerve compression. The extent of decreased
action potentials correlates with prognosis.
o Prolonged distal latencies may be present.
o Rarely neurophysiologic testing is normal in patients with GBS. This is
believed to be due to the location of demyelinating lesions in proximal
sites not amenable to study.

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 Muscle biopsy may help to distinguish GBS from a primary myopathy in unclear
cases.
Many different abnormalities may be seen on ECG, including second-degree and
third-degree atrioventricular (AV) block, T-wave abnormalities, ST depression,
QRS widening, and a variety of rhythm disturbances.

Procedures
Lumbar puncture and spinal fluid analysis

Prehospital Care
ABCs, IV, oxygen, and assisted ventilation may be indicated.
Monitor for cardiac arrhythmias.
Transport expeditiously.

Emergency Department Care

ABCs, IV, oxygen, and assisted ventilation may be indicated.
Intubation should be performed on patients who develop any degree of respiratory
failure. Clinical indicators of the need for intubation include hypoxia, rapidly
declining respiratory function, poor or weak cough, and suspected aspiration.
Typically, intubation is indicated when the FVC is less than 15 mL/kg.24
Patients who have, or are suspected of having, GBS should be monitored closely
for changes in blood pressure, heart rate, and other arrhythmias.

o Treatment rarely is needed for tachycardia.
o Atropine is recommended for symptomatic bradycardia.
o Because of the lability of dysautonomia, hypertension is best treated with
short-acting agents, such as a short-acting beta-blocker or nitroprusside.
o Hypotension of dysautonomia usually responds to intravenous fluids and
supine positioning.
o Temporary pacing may be required for patients with second-degree and
third-degree heart block.

Consultations
Consult a neurologist if any uncertainty exists as to the diagnosis.
Consult the ICU team for evaluation of need for admission to the unit.

MEDICATION

Only plasma exchange (PE) therapy and intravenous immune serum globulin (IVIG)
have proven effective. Both therapies have been shown to shorten recovery time by as
much as 50%. IVIG is easier to administer and has fewer complications than plasma
exchange.25 The cost and efficacy of the 2 treatments are comparable.

Randomized trials in severe disease show that IVIG started within 4 weeks from onset

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hastens recovery as much as plasma exchange.26, 27, 28, 29 Combining plasma exchange and
IVIG neither improved outcomes nor shortened the duration of illness.30 IVIG has also
been proven safe and effective in the treatment of pediatric GBS.30, 31 Additionally, IVIG
is the preferential treatment in hemodynamically unstable patients and in those unable to
ambulate independently.32, 30

Corticosteroids are ineffective as monotherapy.2, 5 Limited evidence shows that oral

corticosteroids significantly slow recovery from GBS.27 Substantial evidence shows that
intravenous methylprednisolone alone does not produce significant benefit or harm. In
combination with IVIG, intravenous methylprednisolone may hasten recovery but does
not significantly affect the long-term outcome.27, 33

Immunoadsorption is an alternative that is still in the early stages of investigation. A

small prospective study showed no difference in outcome between patients treated with
immunoadsorption and those treated with plasma exchange.34

Interferon beta was not associated with significant clinical improvement compared with
controls in a small randomized control trial.35

Simple analgesics or nonsteroidal anti-inflammatory drugs may be tried but often do not
provide adequate pain relief. Single, small randomized controlled trials support the use of
gabapentin or carbamazepine in the intensive care unit for the treatment of pain in the
acute phase of GBS. Adjuvant therapy with tricyclic antidepressant medication, tramadol,
gabapentin, carbamazepine, or mexiletine may aid in the long-term management of
neuropathic pain.36

Time to development of deep vein thrombosis (DVT) or pulmonary embolism varies

from 4-67 days following symptom onset. 36 DVT prophylaxis with gradient compression
hose and subcutaneous low molecular weight heparin (LMWH) may cause a dramatic
reduction in the incidence of venous thromboembolism, one of the major sequela of
extremity paralysis.36

True gradient compression stockings (30-40 mm Hg or higher) are highly elastic,

providing a gradient of compression that is highest at the toes and gradually decreases to
the level of the thigh. This reduces capacity venous volume by approximately 70% and
increases the measured velocity of blood flow in the deep veins by a factor of 5 or more.

The ubiquitous white stockings known as antiembolic stockings or thromboembolic

disease (TED) hose produce a maximum compression of 18 mm Hg and rarely are fitted
in such a way as to provide adequate gradient compression. They have not been shown to
be effective as prophylaxis against thromboembolism.

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Drug Category: Blood product derivatives

These agents are used to improve the clinical and immunologic aspects of the disease.
They may decrease autoantibody production and increase solubilization and removal of
immune complexes.

Further Inpatient Care

Admission to the ICU should be considered for all patients with labile
dysautonomia, an FVC of less than 20 mL/kg, or severe bulbar palsy.36
Any patients exhibiting clinical signs of respiratory compromise, in any degree,
also should be admitted to an ICU.36
The risk of sepsis and infection can be decreased by use of minimal sedation,
frequent physiotherapy, and mechanical ventilation with positive end expiratory
pressure where appropriate.36
The risk of DVT and pulmonary embolus may be minimized by administration of
heparin or a low molecular weight heparin and intermittent pneumatic
compression devices.36
The use of cardiac telemetry and pacing in the case of severe bradycardia may
help to reduce the risk of cardiac morbidity and mortality.36
Pain may be symptomatically improved by frequent passive limb movements,
gentle massage, frequent position changes, and use of carbamazepine and
gabapentin.37, 36
Narcotics should be used judiciously because patients may already be at risk for
ileus.36

Further Outpatient Care

Physical therapy and occupational therapy may be beneficial in helping patients to
regain their baseline functional status.9, 36

Transfer
Transfer may be appropriate if a facility does not have the proper resources to
care for patients who may require prolonged intubation or prolonged intensive
care.

Complications
With modern methods of respiratory management, most complications result from
long-term paralysis. Possible complications include the following:

o Persistent paralysis
o Respiratory failure, mechanical ventilation
o Hypotension or hypertension
o Thromboembolism, pneumonia, skin breakdown
o Cardiac arrhythmia
o Ileus
o Aspiration

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 o Urinary retention
o Psychiatric problems such as depression and anxiety
o Nephropathy reported in pediatric patients38

Prognosis
Poor prognosis is associated with rapid progression of symptoms, advanced age,
prolonged ventilation (>1 mo), and severe reduction of action potentials on
neuromuscular testing.
Published reports indicate full recovery may be expected in 50-95% of cases.
Increased CSF levels of neurone-specific enolase and S-100b protein are
associated with longer duration of illness.1
A longer-lasting increase in IgM anti-GM1 predicts slow recovery.1
Neurologic sequelae

o Reported incidence of permanent neurologic sequelae ranges from 10-
40%.
o The worst-case scenario is tetraplegia within 24 hours with incomplete
recovery after 18 months or longer.
o The best-case scenario is mild difficulty walking, with recovery within
weeks.
o The usual scenario is peak weakness in 10-14 days with recovery in weeks
to months. Average time on a ventilator (without treatment) is 50 days.
Mortality

o Most is due to severe autonomic instability or from the complications of
prolonged intubation and paralysis.39, 40, 41, 23
o Mortality rates range from 5-10%.

Special Concerns
The leading cause of death in elderly patients with GBS is arrhythmia.
Recurrence is rare but has been reported in 2-5% of patients.42
Variants may present with pure motor dysfunction or acute dysautonomia.
The Miller-Fisher syndrome is a variant of GBS in which the initial symptoms
include ataxia, ophthalmoplegia, and areflexia.

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