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Guillain-Barre Syndrome

Background
Guillain-Barr syndrome (GBS) may be described as a collection of clinical syndromes
that manifests as an acute inflammatory polyradiculoneuropathy with resultant weakness
and diminished reflexes. With poliomyelitis under control in developed countries, GBS is
now the most important cause of acute flaccid paralysis.
Although the classic description of GBS is that of a demyelinating neuropathy with
ascending weakness, many clinical variants have been well documented in the medical
literature. Acute inflammatory demyelinating polyradiculoneuropathy is the most widely
recognized form in Western countries, but the variants known as acute motor axonal
neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN) also are
well recognized.
Based on a clinical spectrum of symptoms and findings, many believe that strictly
defined subgroups of GBS exist. However, these subgroups are not easily distinguished.
GBS remains a diagnosis made primarily through the assessment of clinical history and
findings (see Clinical). Serum autoantibodies are not measured routinely in the workup of
GBS, but results may be helpful in patients with a questionable diagnosis or a variant of
GBS (see Workup).
Approximately one third of patients require admission to an intensive care unit, primarily
because of respiratory failure. After medical stabilization, patients can be treated on a
general medical/neurologic floor, but continued vigilance remains important in
preventing respiratory, cardiovascular, and other medical complications. Treatment with
intravenous immunoglobulin or plasma exchange may hasten recovery. (See Treatment.)

Historical background
In 1859, Landry published a report on 10 patients with an ascending paralysis.[1]
Subsequently, in 1916, 3 French physicians (Guillain, Barr, and Strohl) described 2
French soldiers with motor weakness, areflexia, cerebrospinal fluid (CSF)
albuminocytological dissociation, and diminished deep tendon reflexes.[2] The identified
syndrome was later named Guillain-Barr syndrome. Historically, GBS was a single
disorder; however, current practice acknowledges several variant forms.

Pathophysiology

GBS is a postinfectious, immune-mediated disease. Cellular and humoral immune


mechanisms probably play a role in its development. Most patients report an infectious
illness in the weeks prior to the onset of GBS. Many of the identified infectious agents
are thought to induce production of antibodies that cross-react with specific gangliosides
and glycolipids, such as GM1 and GD1b, that are distributed throughout the myelin in the
peripheral nervous system.[3]
The pathophysiologic mechanism of an antecedent illness and of GBS can be typified by
Campylobacter jejuni infections.[4, 5] The virulence of C jejuni is thought to be based on
the presence of specific antigens in its capsule that are shared with nerves.
Immune responses directed against lipopolysaccharide antigens in the capsule of C jejuni
result in antibodies that cross-react with ganglioside GM1 in myelin, resulting in the
immunologic damage to the peripheral nervous system. This process has been termed
molecular mimicry.[6, 7]
Pathologic findings in GBS include lymphocytic infiltration of spinal roots and peripheral
nerves (cranial nerves may be involved as well), followed by macrophage-mediated,
multifocal stripping of myelin. This phenomenon results in defects in the propagation of
electrical nerve impulses, with eventual absence or profound delay in conduction, causing
flaccid paralysis. Recovery is typically associated with remyelination.
In some patients with severe disease, a secondary consequence of the severe
inflammation is axonal disruption and loss. A subgroup of patients may have a primary
immune attack directly against nerve axons, with sparing of myelin. The clinical
presentation in these patients is similar to that of the principal type.
Subtypes of Guillain-Barr syndrome
Several variants of GBS are recognized. These disorders share similar patterns of
evolution, symptom overlap, and probable immune-mediated pathogenesis. Recovery
varies.
Acute inflammatory demyelinating polyneuropathy
The acute inflammatory demyelinating polyneuropathy (AIDP) subtype is the most
commonly identified form in the United States. It is generally preceded by a bacterial or
viral infection. Nearly 40% of patients are seropositive for C jejuni. Lymphocytic
infiltration and macrophage-mediated peripheral nerve demyelination is present.
Symptoms generally resolve with remyelination.
Acute motor axonal neuropathy
The acute motor axonal neuropathy (AMAN) subtype is a purely motor disorder that is
more prevalent in pediatric age groups.[8] AMAN is generally characterized by rapidly
progressive symmetric weakness and ensuing respiratory failure.

Nearly 70-75% of patients are seropositive for Campylobacter. Patients typically have
high titers of antibodies to gangliosides (ie, GM1, GD1a, GD1b). Inflammation of the
spinal anterior roots may lead to disruption of the blood-CNS barrier.[6] Biopsies show
wallerianlike degeneration without significant lymphocytic inflammation.
Many cases have been reported in rural areas of China, especially in children and young
adults during the summer months.[9] Pure axonal cases may occur more frequently outside
of Europe and North America. AMAN cases may also be different from cases of axonal
GBS described in the West.
Prognosis is often quite favorable. Although recovery for many is rapid, severely disabled
patients with AMAN may show improvement over a period of years.[10]
One third of patients with AMAN may actually be hyperreflexic. The mechanism for this
hyperreflexia is unclear; however, 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]
Acute motor-sensory axonal neuropathy
Acute motor-sensory axonal neuropathy (AMSAN) is an acute severe illness differing
from AMAN in that AMSAN also affects sensory nerves and roots.[11] Patients are
typically adults. AMSAN often presents as rapid and severe motor and sensory
dysfunction. Marked muscle wasting is characteristic, and recovery is poorer than from
electrophysiologically similar AMAN cases.
Like AMAN, AMSAN also is associated with preceding C jejuni diarrhea. Pathologic
findings show severe axonal degeneration of motor and sensory nerve fibers with little
demyelination.[12]
Miller-Fisher syndrome
Miller-Fisher syndrome (MFS), which is observed in about 5% of all GBS cases,
classically presents as the triad of ataxia, areflexia, and ophthalmoplegia.[13] Acute onset
of external ophthalmoplegia is a cardinal feature.[6] 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. Patients have reduced or absent sensory nerve action potentials and
absent tibial H reflex.[14]
Anti-GQ1b antibodies are prominent in MFS, and have a relatively high specificity and
sensitivity for the disease.[15] Dense concentrations of GQ1b ganglioside are found in the
oculomotor, trochlear, and abducens nerves, which may explain the relationship between
anti-GQ1b antibodies and ophthalmoplegia. Patients with acute oropharyngeal palsy
carry anti-GQ1b/GT1a IgG antibodies.[6] Recovery generally occurs within 1-3 months.
Acute panautonomic neuropathy

Acute panautonomic neuropathy, the rarest GBS variant, involves both the sympathetic
and parasympathetic nervous systems. Patients have severe postural hypotension, bowel
and bladder retention, anhidrosis, decreased salivation and lacrimation, and pupillary
abnormalities. Cardiovascular involvement is common, and dysrhythmias are a
significant source of mortality. Significant motor or sensory involvement is lacking.
Recovery is gradual and often incomplete.
Pure sensory Guillain-Barr syndrome
A pure sensory variant of GBS has been described in the literature. It is typified by a
rapid onset of sensory loss and areflexia in a symmetric and widespread pattern. Lumbar
puncture studies show albuminocytologic dissociation in the CSF, and electromyography
(EMG) results show characteristic signs of a demyelinating process in the peripheral
nerves.
Prognosis is generally good. Immunotherapies, such as plasma exchange and the
administration of intravenous immunoglobulins (IVIGs), can be tried in patients with
severe disease or slow recovery.
Other variants
The pharyngeal-cervical-brachial variant of GBS is distinguished by isolated facial,
oropharyngeal, cervical, and upper limb weakness without lower limb involvement.
Other unusual clinical variants with restricted patterns of weakness are observed only in
rare cases.

Etiology
GBS is considered to be a postinfectious, immune-mediated disease targeting peripheral
nerves. Up to two thirds of patients report an antecedent bacterial or viral illness prior to
the onset of neurologic symptoms.[16, 17] Respiratory infections are most frequently
reported, followed by gastrointestinal infections.[18] Administration of certain vaccinations
and other systemic illnesses have also been associated with GBS. Case reports exist
regarding numerous medications and procedures; however, whether any causal link exists
is unclear.
In several studies, C jejuni was the most commonly isolated pathogen. Serology studies
in a Dutch GBS trial identified 32% of patients as having had a recent C jejuni infection,
while studies in northern China documented infection rates as high as 60%.[9, 19]
Gastrointestinal and upper respiratory tract symptoms can be observed with C jejuni
infections. C jejuni infections can also have a subclinical course, resulting in patients
with no reported infectious symptoms prior to development of GBS. Patients who
develop GBS following an antecedent C jejuni infection often have a more severe course,
with rapid progression and a prolonged, incomplete recovery. A strong clinical

association has been noted between C jejuni infections and the pure motor and axonal
forms of GBS.
The virulence of C jejuni is thought to result from the presence of specific antigens in its
capsule that are shared with nerves. Immune responses directed against capsular
lipopolysaccharides produce antibodies that cross-react with myelin to cause
demyelination.
C jejuni infections demonstrate significant association with antibodies against
gangliosides GM1 and GD1b.[20] Although GM1 antibodies can be found in patients with
demyelinating GBS, GM1 antibodies are more common in the axonal and inexcitable
groups. Even in the subgroup of patients with GM1 antibodies, however, the clinical
manifestations vary. Host susceptibility is probably one determinant in the development
of GBS after infectious illness.[19]
Cytomegalovirus (CMV) infections are the second most commonly reported infections
preceding GBS; they account for the most common viral triggers of GBS. The
aforementioned Dutch GBS study found CMV to be present in 13% of patients.[21]
CMV infections present as upper respiratory tract infections, pneumonias, and
nonspecific flulike illnesses. GBS patients with preceding CMV infections often have
prominent involvement of the sensory and cranial nerves. CMV infections are
significantly associated with antibodies against the ganglioside GM2.
Other significant, although less frequently identified, infectious agents in GBS patients
include Epstein-Barr virus (EBV), Mycoplasma pneumoniae, and varicella-zoster virus.
[22]
An association between GBS and acute human immunodeficiency virus (HIV)
infection also is well recognized.[1, 23, 24, 25, 26]
Infections with Haemophilus influenzae, Borrelia burgdorferi, para-influenza virus type
1, influenza A virus, influenza B virus, adenovirus, and herpes simplex virus have been
demonstrated in patients with GBS, although not more frequently than they have in
controls.[27]
Various events, such as surgery, trauma, and pregnancy, have been reported as possible
triggers of GBS, but these associations remain mostly anecdotal.

Vaccines
Vaccinations have been linked to GBS,[28] by temporal association. In most cases,
however, no definite causal relation has been established between vaccines and GBS
(with the exception of rabies vaccine prepared from infected brain tissue and the 1976
swine flu vaccine. Subsequent surveys have found no significantly increased incidence of
GBS after vaccination programs.[29, 27]

A review of all post-vaccination cases of GBS from 1990-2005 did not reveal an increase
in mortality with postvaccination cases of GBS compared with cases by other causes.[28]
A study reviewing GBS cases during the 1992-1993 and 1993-1994 influenza seasons
found an adjusted relative risk of 1.7 cases per 1 million influenza vaccinations.[30]
Recent studies found no evidence of an increased risk of GBS after seasonal influenza
vaccine, or after the 2009 H1N1 mass vaccination program.[31, 32, 33] This is further
supported by a study conducted by the Chinese Centers for Disease Control in which 89.6
million doses of vaccine were administered from September 21, 2009, through March 21,
2010. This study also noted no evidence of an increased risk of GBS following H1N1
vaccination.[34]
Additionally, a study by Dieleman et al researched the association between the pandemic
influenza A (H1N1) 2009 vaccine and GBS in 104 patients in 5 European countries.
Adjusting for the effects of influenzalike illness/upper respiratory tract infection, seasonal
influenza vaccination, and calendar time, the authors concluded that there was not an
increased risk of occurrence of GBS after receiving the pandemic influenza vaccine.[35]
Epidemiologic studies from Finland and southern California failed to validate an earlier
retrospective study from Finland that suggested a cause-effect relationship between oral
polio vaccination and GBS.[36, 37] In contrast, a Brazilian study suggested that, based on a
temporal association between the vaccine and the onset of GBS, the vaccine may rarely
correlate with GBS.[38]
Data from a large-scale epidemiologic study reported a decreased GBS incidence
following administration of tetanus toxoid containing vaccinations when compared with
the baseline population.[39]
An epidemiologic study failed to show any conclusive epidemiologic association between
GBS and the hepatitis B vaccine.[40]
A large Latin American study of more than 2000 children with GBS following a mass
measles vaccination program in 1992-1993 failed to establish a statistically significant
causal relationship between administration of the measles vaccine and GBS.[41]
A report from the US Centers for Disease Control and Prevention (CDC) suggests that
recipients of the Menactra meningococcal conjugate vaccine may be at increased risk of
GBS.[42]
Case reports exist regarding group A streptococcal vaccines and the rabies vaccine.
However, conclusive statistically significant evidence is lacking.

Medications

In a case-controlled study, GBS patients reported more frequent penicillin and


antimotility drug use, and less frequent oral contraceptive use. No definite cause-effect
relationship has been established.[43]
Case reports exist in the setting of tumor necrosis factor antagonist agents used in
rheumatoid arthritis.[44, 45, 46, 47] Case reports exist regarding streptokinase, isotretinoin,
danazol, captopril, gold, and heroin, among others.

Other associations
Case reports cite associations between bariatric and other gastric surgeries, renal
transplantation, and epidural anesthesia.[48]
Anecdotal associations include systemic lupus erythematosus, sarcoidosis, lymphoma,
and snakebite.
Tumor necrosis factoralpha polymorphisms with increased expression are associated
with many autoimmune and inflammatory diseases, and may increase susceptibility to
axonal GBS subtypes. However, the role of these polyphorphisms in GBS remains
unclear and warrants further investigation.[49]

Epidemiology
United States statistics
The annual incidence of GBS is 1.2-3 per 100,000 inhabitants, making GBS the most
common cause of acute flaccid paralysis in the United States.[1, 2, 23, 50] In comparing age
groups, the annual mean rate of hospitalizations in the United States related to GBS
increases with age, being 1.5 cases per 100,000 population in persons aged less than 15
years and peaking at 8.6 cases per 100,000 population in persons aged 70-79 years.[51]
US military personnel are at slightly increased risk of GBS compared with the general
population. An antecedent episode of infectious gastroenteritis was a significant risk
factor for the development of GBS among military personnel.[18]

International statistics
GBS has been reported throughout the world.[52, 53] Most studies show annual incidence
figures similar to those in the United States, without geographical clustering. AMAN and
AMSAN occur mainly in northern China, Japan, and Mexico, and they comprise 5-10%
percent of GBS cases in the United States.[54] Acute inflammatory demyelinating
polyradiculoneuropathy 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 CMV infections compared with that in North America and Europe.
Similarly, it has been reported that 69% of GBS cases in Dhaka, Bangladesh, have
clinical evidence of antecedent C jejuni infection.[24]

Race-, sex-, and age-related demographics


GBS has been reported throughout the international community; no racial preponderance
exists. In North America, Western Europe, and Australia, most patients with GBS meet
electrophysiologic criteria for demyelinating polyneuropathy. In northern China, up to
65% of patients with GBS have axonal pathology.[9]
GBS has a male-to-female ratio of 1.5:1; male preponderance is seen especially in older
patients. However, a Swedish epidemiologic study reported that GBS rates decrease
during pregnancy and increase in the months immediately following delivery.[55]
GBS has been reported in all age groups, with the syndrome occurring at any time
between infancy and old age. In the United States, the syndrome's age distribution seems
to be bimodal, with a first peak in young adulthood (age 15-35 y) and a second, higher
one in elderly persons (age 50-75 y). Infants appear to have the lowest risk of developing
GBS.[56]

Prognosis
Although most patients with GBS make good recovery, 2-12% of them die from
complications related to GBS, and a significant percentage of survivors have persistent
motor sequelae. The mortality rate 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 acute respiratory distress syndrome, sepsis, pneumonia, venous
thromboembolic disease, and cardiac arrest. Most cases of mortality are due to severe
autonomic instability or from the complications of prolonged intubation and paralysis.[57,
58, 59, 60]
The leading cause of death in elderly patients with GBS is arrhythmia.
GBS-associated mortality rates increase markedly with age. In the United States, the
case-fatality ratio ranges from 0.7% among persons younger than 15 years to 8.6%
among individuals older than 65 years. Survey data has shown that in patients aged 60
years or older, the risk of death is 6-fold that of persons aged 40-59 years and is 157-fold
that of patients younger than 15 years. Although the death rate increases with age in
males and females, after age 40 years males have a death rate that is 1.3 times greater
than that of females.
GBS-related deaths usually occur in ventilator-dependent patients, resulting from such
complications as pneumonia, sepsis, adult respiratory distress syndrome, and, less
frequently, autonomic dysfunction.[61] Underlying pulmonary disease and the need for

mechanical ventilation increase the risk of death, especially in elderly patients. Length of
hospital stays also increases with advancing age, because of disease severity and
associated medical complications.
Most patients (up to 85%) with GBS achieve a full and functional recovery within 6-12
months. Recovery is maximal by 18 months.[62] Estimates indicate 15-20% of patients
have moderate residual deficits, and 1-10% are left severely disabled.
Although the exact prevalence is uncertain, up to 25,000-50,000 persons in the United
States may have long-term functional deficits from GBS. The reported incidence of
permanent neurologic sequelae ranges from 10-40%.[63]
Patients may experience 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. Patients may
also exhibit long-term differences in pain intensity, fatigability, and functional
impairment compared with healthy controls.[64]
Short of death, the worst-case scenario is tetraplegia within 24 hours with incomplete
recovery after 18 months or longer. The best-case scenario is mild difficulty walking,
with recovery within weeks. 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.
The speed of recovery varies. Recovery often takes place within a few weeks or months;
however, if axonal degeneration has occurred, recovery can be expected to progress
slowly over many months, because regeneration may require 6-18 months.
The following factors have been associated with adverse effect on outcomes in GBS[65, 66,
67]
:

Preceding gastrointestinal infection


Older age
Poor upper extremity muscle strength
Acute hospital stay of longer than 11 days
Intensive care unit requirement
Need for mechanical ventilation
Medical Research Council (MRC) score < 40
Discharge to rehabilitation

A rapidly progressing onset of weakness also has been associated with less favorable
outcomes in many studies, although in other reports, delayed time to peak disability has
been shown to be an independent predictor of poor outcome at 1 year.
Low mean compound muscle action potential (CMAP) amplitudes of less than 20% of
the lower limit of normal or the presence of inexcitable nerves on initial
electrophysiologic studies are other predictors of poorer functional outcomes. Persistence

of a low mean CMAP on later testing (>1 mo after onset) results in an even higher
sensitivity and specificity of testing than does the initial test after onset.
A prospective, multicenter study by Petzold et al suggested that CSF levels of high
molecular weight neurofilament (NfH) protein, an axonal protein, are prognostic
indicators in GBS.[68] The investigators found that among patients with GBS who suffered
a poor outcome (defined as an inability to walk independently), the median NfH level
was 1.78 ng/ml; in patients with GBS who had a good outcome, the median level was
0.03 ng/ml.
Increased CSF levels of neuron-specific enolase and S-100b protein are also associated
with longer duration of illness.[1] Serologically, a longer-lasting increase in IgM anti-GM1
predicts slow recovery.[1]
The presence of underlying pulmonary disease or manifestation of dysautonomia has no
prognostic significance in GBS.
In a small percentage (~10%) of patients, an acute relapse occurs after initial
improvement or stabilization after treatment. Some patients also demonstrate treatment
fluctuations during their clinical course. Recurrence of Guillain-Barr syndrome is rare
but has been reported in 2-5% of patients.[69, 70]
There is no convincing evidence that intravenous immunoglobulin (IVIG) treatment or
plasma exchange has a significant effect on the rate of treatment failure or of acute
relapse.[71] The risk of relapse does appear to be higher in patients in whom there has been
a later onset of treatment, a more protracted disease course, and more associated medical
conditions. Additional plasma exchange or IVIG treatments often result in further
improvement.[72]

Patient Education
Patients with GBS and their families should be educated on the illness, the disease
process, and the anticipated course. GBS is a life event with a potentially long-lasting
influence on patients' physical and psychosocial well-being.[73, 74, 75] Family education and
training also is recommended to prevent complications during the early stages of the
disease and to assist in the recovery of function during the rehabilitation stages.
For patient education information, see the Brain and Nervous System Center, as well as
Guillain-Barr Syndrome.

History
The typical patient with Guillain-Barr syndrome (GBS), which in most cases will be
acute demyelinating polyradiculoneuropathy (AIDP), presents 2-4 weeks following a
relatively benign respiratory or gastrointestinal illness with complaints of finger

dysesthesias and proximal muscle weakness of the lower extremities. The weakness may
progress over hours to days to involve the arms, truncal muscles, cranial nerves, and
muscles of respiration. Variants of Guillain-Barr syndrome may present as pure motor
dysfunction or acute dysautonomia.
The mean time to the clinical function nadir is 12 days, with 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.[76] Progression of symptoms
beyond that point brings the diagnosis under question. Recovery usually begins 2-4
weeks after the progression ceases.[77] The mean time to clinical recovery is 200 days.

Weakness
The classic clinical picture of weakness is ascending and symmetrical in nature. The
lower limbs are usually involved before the upper limbs. Proximal muscles may be
involved earlier than the more distal ones. Trunk, bulbar, and respiratory muscles can be
affected as well.
Patients may be unable to stand or walk despite reasonable strength, especially when
ophthalmoparesis or impaired proprioception is present. Respiratory muscle weakness
with shortness of breath may be present.
Weakness develops acutely and progresses over days to weeks. Severity may range from
mild weakness to complete tetraplegia with ventilatory failure.

Cranial nerve involvement


Cranial nerve involvement is observed in 45-75% of patients with GBS. Cranial nerves
III-VII and IX-XII may be affected. Common complaints may include the following:

Facial droop (may mimic Bell palsy)


Diplopias
Dysarthria
Dysphagia
Ophthalmoplegia
Pupillary disturbances

Facial and oropharyngeal weakness usually appears after the trunk and limbs are affected.
The Miller-Fisher variant of GBS is unique in that this subtype begins with cranial nerve
deficits.[78]

Sensory changes
Most patients complain of paresthesias, numbness, or similar sensory changes. Sensory
symptoms often precede the weakness. Paresthesias generally begin in the toes and

fingertips, progressing upward but generally not extending beyond the wrists or ankles.
Loss of vibration, proprioception, touch, and pain distally may be present.
Sensory symptoms are usually mild. In most cases, objective findings of sensory loss
tend to be minimal and variable.

Pain
In a prospective, longitudinal study of pain in patients with GBS, 89% of patients
reported pain that was attributable to GBS at some time during their illness. On initial
presentation, almost 50% of patients described the pain as severe and distressing. The
mechanism of pain is uncertain and may be a product of several factors. Pain can result
from direct nerve injury or from the paralysis and prolonged immobilization.
Pain is most severe in the shoulder girdle, back, buttocks, and thighs and may occur with
even the slightest movements. The pain is often described as aching or throbbing in
nature.
Dysesthetic symptoms are observed in approximately 50% of patients during the course
of their illness. Dysesthesias frequently are described as burning, tingling, or shocklike
sensations and are often more prevalent in the lower extremities than in the upper
extremities. Dysesthesias may persist indefinitely in 5-10% of patients.
Other pain syndromes in GBS include the following:

Myalgic complaints, with cramping and local muscle tenderness


Visceral pain
Pain associated with conditions of immobility (eg, pressure nerve palsies,
decubitus ulcers)

The intensity of pain on admission correlates poorly with neurologic disability on


admission and with the end outcome.

Autonomic changes
Autonomic nervous system involvement with dysfunction in the sympathetic and
parasympathetic systems can be observed in patients with GBS.
Autonomic changes can include the following:

Tachycardia
Bradycardia
Facial flushing
Paroxysmal hypertension
Orthostatic hypotension
Anhidrosis and/or diaphoresis

Urinary retention due to urinary sphincter disturbances may be noted. Constipation due to
bowel paresis and gastric dysmotility may be present. Bowel and bladder dysfunction are
rarely early or persistent findings.
Dysautonomia is more frequent in patients with severe weakness and respiratory failure.
Autonomic changes rarely persist in a patient with GBS.

Respiratory involvement
Upon presentation, 40% of patients have respiratory or oropharyngeal weakness. Typical
complaints include the following:

Dyspnea on exertion
Shortness of breath
Difficulty swallowing
Slurred speech

Ventilatory failure with required respiratory support occurs in up to one third of patients
at some time during the course of their disease.

Antecedent illness
Up to two thirds of patients with GBS report an antecedent illness or event 1-3 weeks
prior to the onset of weakness. Upper respiratory and gastrointestinal illnesses are the
most commonly reported conditions.[16, 18] Symptoms generally have resolved by the time
the patient presents for the neurologic condition.
Campylobacter jejuni is the major causative organism identified in most studies and is
responsible for cases of AIDP and acute motor axonal neuropathy (AMAN). In one major
study, previous diarrheal illness had occurred in 60% of patients with axonal GBS (by
neurophysiologic testing).
Vaccinations, surgical procedures, and trauma have been reported to trigger the
development of GBS.[28] Much of this information is anecdotal, although vaccination with
the swine flu vaccine administered in 1976 was shown to increase the risk of contracting
GBS to a small, but definable, degree. Rabies vaccine prepared from infected brain tissue
also was found to have an association with GBS. Studies of other vaccines, however,
have not shown a significant relationship between these drugs and GBS.[29, 35]

Physical Examination
Cardiac arrhythmias, including tachycardias and bradycardias, can be observed as a result
of autonomic nervous system involvement. Tachypnea may be a sign of ongoing dyspnea
and progressive respiratory failure.

Blood pressure lability is another common feature, with alterations between hypertension
and hypotension. Temperature may be elevated or low.
Respiratory examination may be remarkable for poor inspiratory effort or diminished
breath sounds. On abdominal examination, paucity or absence of bowel sounds suggests
paralytic ileus. Suprapubic tenderness or fullness may be suggestive of urinary retention.

Neurologic examination
Facial weakness (cranial nerve VII) is observed most frequently, followed by symptoms
associated with cranial nerves VI, III, XII, V, IX, and X. Involvement of facial,
oropharyngeal, and ocular muscles results in facial droop, dysphagia, dysarthria, and
findings associated with disorders of the eye.
Ophthalmoparesis may be observed in up to 25% of patients with GBS. Limitation of eye
movement most commonly results from a symmetric palsy associated with cranial nerve
VI. Ptosis from cranial nerve III (oculomotor) palsy also is often associated with limited
eye movements. Pupillary abnormalities, especially those accompanying
ophthalmoparesis, are relatively common as well. Papilledema secondary to elevated
intracranial pressure is present in rare cases. Tonic pupils have been reported but only in
severe cases.
Lower extremity weakness usually begins first and ascends symmetrically and
progressively over the first several days. Upper extremity, trunk, facial, and
oropharyngeal weakness is observed to a variable extent. Marked asymmetric weakness
calls the diagnosis of GBS into question.
Patients may be unable to stand or walk despite reasonable strength, especially when
ophthalmoparesis or impaired proprioception is present.
Despite frequent complaints of paresthesias, objective sensory changes are minimal. A
well-demarcated sensory level should not be observed in patients with GBS; such a
finding calls the diagnosis of GBS into question.
Reflexes are absent or reduced early in the disease course. Hyporeflexia or areflexia of
involved areas represents a major clinical finding on examination of the patient with
GBS. Pathologic reflexes, such as the Babinski sign, are absent. Hypotonia can be
observed with significant weakness.

Diagnostic Considerations
Problems to consider in the differential diagnosis of Guillain-Barr syndrome include the
following:

Acute myelopathy (eg, from compression, transverse myelitis, vascular injury)


Chronic inflammatory demyelinating polyneuropathy

Conversion disorder/hysterical paralysis


HIV peripheral neuropathy
Neurotoxic fish or shellfish poisoning
Paraneoplastic neuropathy
Poliomyelitis
Porphyria polyneuropathy
Spinal cord compression
Spinal cord syndromes, particularly postinfection
Tick paralysis[79]
Toxic neuropathies (eg, arsenic, thallium, organophosphates, lead)
Vasculitic neuropathies
Vitamin deficiency (eg, vitamin B-12, folate, thiamine)
West Nile encephalitis

Differential Diagnoses

Botulism
Cauda Equina and Conus Medullaris Syndromes
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Emergent Management of Myasthenia Gravis
Heavy Metal Toxicity
Lyme Disease
Metabolic Myopathies
Multiple Sclerosis
Nutritional Neuropathy
Vasculitic Neuropathy

Approach Considerations
Guillain-Barr syndrome (GBS) is generally diagnosed on clinical grounds. Basic
laboratory studies, such as complete blood counts and metabolic panels, are of limited
value in the diagnosis of GBS. They are often ordered, however, to exclude other
diagnoses, and to better assess functional status and prognosis. The ordering of specific
tests should be guided by the patient's history and presentation.
Abnormalities in nerve conduction studies (NCS) that are consistent with demyelination
are sensitive and represent specific findings for classic GBS.[80] Frequent evaluations of
these parameters should be performed at bedside to monitor respiratory status and the
need for ventilatory assistance.
Lumbar puncture for cerebrospinal fluid (CSF) studies is recommended. During the acute
phase of GBS, characteristic findings on CSF analysis include albuminocytologic
dissociation, which is an elevation in CSF protein (>0.55 g/L) without an elevation in
white blood cells. The increase in CSF protein is thought to reflect the widespread
inflammation of the nerve roots.

Imaging studies, such as magnetic resonance imaging (MRI) or computed tomography


(CT) scanning of the spine, may be more helpful in excluding other diagnoses, such as
mechanical causes of myelopathy, than in assisting in the diagnosis of GBS.

Peripheral Neuropathy Workup


A basic peripheral neuropathy workup is recommended in cases in which the diagnosis is
uncertain. These studies may include the following:

Thyroid panel
Rheumatology profiles
Vitamin B-12
Folic acid
Hemoglobin A1C
Erythrocyte sedimentation rate (ESR)
Rapid protein reagent
Immunoelectrophoresis of serum protein
Tests for heavy metals

Biochemical Screening
Biochemical screening includes the following studies:

Electrolyte levels
Liver function tests (LFTs)
Creatine phosphokinase (CPK) level
Erythrocyte sedimentation rate (ESR)

LFT results are elevated in as many as one third of patients. CPK and ESR may be
elevated with myopathies or systemic inflammatory conditions. A stool culture for C
jejuni and pregnancy test are also indicated.
The syndrome of inappropriate antidiuretic hormone (SIADH) may occur.

Serologic Studies
Serologic studies are of limited value in the diagnosis of GBS. Assays for antibodies to
the following infectious agents may be considered:

Campylobacter jejuni
Cytomegalovirus
Epstein-Barr virus
Herpes simplex virus (HSV)
HIV

Mycoplasma pneumoniae

An increase in titers for infectious agents, such as CMV, EBV, or Mycoplasma, may help
in establishing etiology for epidemiologic purposes. HIV has been reported to precede
GBS, and serology should be tested in high-risk patients to establish possible infection
with this agent.

Serum autoantibodies
Serum autoantibodies are not measured routinely in the workup of GBS, but results may
be helpful in patients with a questionable diagnosis or a variant of GBS. Antibodies to
glycolipids are observed in the sera of 60-70% of patients with GBS during the acute
phase, with gangliosides being the major target antigens.[81]
Antibodies to GM1 frequently are frequently found in the sera of patients with the motor
axonal neuropathy or AIDP variants of GBS. Antecedent C jejuni infections are closely
associated with elevated titers of anti-GM1 antibodies. Anti-GQ1b antibodies are found
in patients with GBS with ophthalmoplegia, including patients with the Miller-Fisher
variant. Other antibodies to different major and minor gangliosides also have been found
in GBS patients.

Nerve Conduction Studies


Nerve conduction studies (NCS) can be very helpful in the diagnostic workup of patients
with suspected GBS. Abnormalities in NCS that are consistent with demyelination are
sensitive and represent specific findings for classic GBS.[80]
A delay in F-waves is present, implying nerve root demyelination.[2, 82] Nerve motor action
potentials may be decreased. This is technically difficult to determine until the
abnormality is severe. Compound muscle action potential (CMAP) amplitude may be
decreased. Although most patients exhibit sensory abnormalities on NCS, these findings
are much less marked than they are in motor nerves.
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. Prolonged distal latencies may be present. Abnormal H-reflex may be noted.
Although NCS results classically show a picture of demyelinating neuropathy in most
patients, axonal neuropathy and inexcitable results are found in certain subgroups. The
inexcitable studies may represent either axonopathy or severe demyelination with distal
conduction block.
On NCS, demyelination is characterized by nerve conduction slowing, prolongation of
the distal latencies, prolongation of the F-waves, conduction block, and/or temporal
dispersion. Changes on NCS should be present in at least 2 nerves in regions that are not

typical for those associated with compressive mononeuropathies (preferentially in


anatomically distinct areas, such as an arm and a leg or a limb and the face).
The needle examination is of limited value in GBS. Reduced motor unit recruitment and
absent denervation help to support the suggestion of a demyelinating mechanism,
although the same changes can be observed in early axonal damage with pending
wallerian degeneration. In severe cases, denervation changes may be observed later in the
disease course.
In the axonal variant of the disease, absent or markedly reduced distal compound muscle
action potentials (CMAP) are observed on NCS. On needle examination, profuse and
early denervation potentials also support the conclusion that there has been axonal injury.
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.

Pulmonary Function Tests


Maximal inspiratory pressures and vital capacities are measurements of neuromuscular
respiratory function and predict diaphragmatic strength. Maximal expiratory pressures
also reflect abdominal muscle strength. Frequent evaluations of these parameters should
be performed at bedside to monitor respiratory status and the need for ventilatory
assistance.
Forced vital capacity (FVC) is very helpful in guiding disposition and therapy.[60] Patients
with an FVC of less than 15-20 mL/kg, maximum inspiratory pressure of less than 30 cm
H2 O, or a maximum expiratory pressure of less than 40 cm H2 O generally progress to
require prophylactic intubation and mechanical ventilation. Respiratory assistance should
also be considered when there is a decrease in oxygen saturation (arterial PO2 < 70 mm
Hg).

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

Magnetic Resonance Imaging

MRI is sensitive but nonspecific for diagnosis; however, it may be an effective diagnostic
adjunct.[83, 84] MRI can reveal nerve root enhancement.
Spinal nerve root enhancement with gadolinium is a nonspecific feature seen in
inflammatory conditions and is caused by disruption of the blood-nerve barrier. Selective
anterior nerve root enhancement appears to be strongly suggestive of GBS.[85] The cauda
equina nerve roots are enhanced in 83% of patients.

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

Histologic Findings
Lymphocyte and macrophage infiltration is observed on microscopic examination of
peripheral nerves. Macrophage influx is believed to be responsible for the multifocal
demyelination seen in GBS. A variable degree of wallerian degeneration also can be
observed with severe inflammatory changes. Cellular infiltrates are scattered throughout
the cranial nerves, nerve roots, dorsal root ganglions, and peripheral nerves.

Approach Considerations
Patients who are diagnosed with GBS should be admitted to a hospital for close
monitoring until it has been determined that the course of the disease has reached a
plateau or undergone reversal. Although the weakness may initially be mild and
nondisabling, symptoms can progress rapidly over just a few days. Continued progression
may result in a neuromuscular emergency with profound paralysis, respiratory
insufficiency, and/or autonomic dysfunction with cardiovascular complications.
Approximately one third of patients require admission to an intensive care unit (ICU),
primarily because of respiratory failure. After medical stabilization, patients can be
treated on a general medical/neurologic floor, but continued vigilance remains important
in preventing respiratory, cardiovascular, and other medical complications. Patients with
persistent functional impairments may need to be transferred to an inpatient rehabilitation
unit.
Continued care also is needed to minimize problems related to immobility, neurogenic
bowel and bladder, and pain. Early involvement of allied health staff is recommended.
Early recognition and treatment of GBS also may be important in the long-term
prognosis, especially in the patient with poor clinical prognostic signs, such as older age,
a rapidly progressing course, and antecedent diarrhea.[86]

Immunomodulatory treatment has been used to hasten recovery. Intravenous


immunoglobulin and plasma exchange have proved equally effective.

Intensive Care
Good supportive care is critical in the treatment of patients with GBS.[87] Because most
deaths related to GBS are associated with complications of ventilatory failure and
autonomic dysfunction, many patients with GBS need to be monitored closely in ICUs by
physicians experienced in acute neuromuscular paralysis and its accompanying
complications. Competent intensive care includes the following features:

Respiratory therapy
Cardiac monitoring
Safe nutritional supplementation
Monitoring for infectious complications (eg, pneumonia, urinary tract infections,
septicemia)

Approximately one third of patients with GBS require ventilatory support. Monitoring for
respiratory failure, bulbar weakness, and difficulties with swallowing help to anticipate
complications. Proper positioning of the patient to optimize lung expansion and secretion
management for airway clearance is required to minimize respiratory complications.
Serial assessment of ventilatory status is needed, including measurements of vital
capacity and pulse oximetric monitoring. Respiratory assistance should be considered
when the expiratory vital capacity decreases to less than 18 mL/kg or when a decrease in
oxygen saturation is noted (arterial PO2 < 70 mm Hg). Tracheotomy may be required in a
patient with prolonged respiratory failure, especially if mechanical ventilation is required
for more than 2 weeks.
Close monitoring of heart rate, blood pressure, and cardiac arrhythmias allows early
detection of life-threatening situations. Critically ill patients require continuous telemetry
and close medical supervision in an ICU setting. Antihypertensives and vasoactive drugs
should be used with caution in patients with autonomic instability. Hemodynamic
changes related to autonomic dysfunction are usually transitory, and patients rarely
require long-term medications to treat blood pressure or cardiac problems.
Enteral or parenteral feedings are required for patients on mechanical ventilation to
ensure that adequate caloric needs are met when the metabolic demand is high. Even
patients who are off the ventilator may require nutritional support if dysphagia is severe.
Precautions against dysphagia and dietary manipulations should be used to prevent
aspiration and subsequent pneumonias in patients at risk.
Prevention of secondary complications of immobility is also required. Subcutaneous
unfractionated or low molecular weight heparin and thromboguards are often used in the
treatment of immobile patients to prevent lower-extremity deep venous thrombosis
(DVT) and consequent pulmonary embolism (PE). Prevention of pressure sores and

contractures entails careful positioning, frequent postural changes, and daily range-ofmotion (ROM) exercises.
Pain management with analgesics and adjunct medications also may be needed.
Modalities such as transcutaneous electrical nerve stimulation (TENS) and heat may
prove beneficial in the management of myalgia. Desensitization techniques can be used
to improve the patient's tolerance for activities.
Although bowel and bladder dysfunction is generally transitory, management of these
functions is needed to prevent other complications. Initial management should be directed
toward safe evacuation and the prevention of overdistention. Monitoring for secondary
infections, such as urinary tract infection, also is an area of concern. Nephropathy has
been reported in pediatric patients.[88]
Hospitalized patients with GBS may experience mental status changes, including
hallucinations, delusions, vivid dreams, and sleep abnormalities.[89] These occurrences are
thought to be associated with autonomic dysfunction and are more frequent in patients
with severe symptoms. Such problems resolve as the patient recovers. Psychiatric
problems such as depression and anxiety may also occur.

Physical Therapy
Estimates suggest that approximately 40% of patients who are hospitalized with GBS
require inpatient rehabilitation. Unfortunately, no long-term rehabilitation outcome
studies have been conducted, and treatment is often based on experiences with other
neurologic conditions. The goals of the therapy programs are to reduce functional deficits
and to target impairments and disabilities resulting from GBS.
Early in the acute phase of GBS, patients may not be able to fully participate in an active
therapy program. At that stage, patients benefit from daily ROM exercises and proper
positioning to prevent muscle shortening and joint contractures. Addressing upright
tolerance and endurance also may be a significant issue during the early part of
rehabilitation.
Active muscle strengthening can then be slowly introduced and may include isometric,
isotonic, isokinetic, or progressive resistive exercises. Mobility skills, such as bed
mobility, transfers, and ambulation, are targeted functions. Patients should be monitored
for hemodynamic instability and cardiac arrhythmias, especially upon initiation of the
rehabilitation program. The intensity of the exercise program also should be monitored,
because overworking the muscles may, paradoxically, lead to increased weakness.
In a study by Gupta et al in 35 patients (27 with classic GBS and 8 with acute motor
axonal neuropathy), GBS-related deficits included neuropathic pain requiring medication
therapy (28 patients), foot drop necessitating ankle-foot orthosis (AFO) use (21 patients),
and locomotion difficulties requiring assistive devices (30 patients). At 1-year follow-up,

the authors found continued foot drop in 12 of the AFO patients. However, significant
overall functional recovery had occurred within the general cohort.[90]

Occupational and Recreational Therapy


Occupational therapy professionals should be involved early in the rehabilitation program
to promote upper body strengthening, ROM, and activities that aid functional self-care.
Both restorative and compensatory strategies can be used to promote functional
improvements. Energy conservation techniques and work simplification also may be
helpful, especially if the patient demonstrates poor strength and endurance.
Participation in recreational therapy assists in the patient's adjustment to disability and
improves integration into the community. Recreational activities, either new or adapted,
can be used to promote the growth, development, and independence of a long-term
hospital patient.

Speech Therapy
Speech therapy is aimed at promoting speech and safe swallowing skills for patients who
have significant oropharyngeal weakness with resultant dysphagia and dysarthria. In
ventilator-dependent patients, alternative communication strategies also may need to be
implemented.
Once weaned from the ventilator, patients with tracheostomies can learn voicing
strategies and can eventually be weaned from the tracheostomy tube. Cognitive screening
also can be performed conjointly with neuropsychology to assess for deficits, since
cognitive problems have been reported in some patients with GBS, especially those who
have had an extended ICU stay.

Immunotherapy
Plasma exchange, carried out over a 10-d period, may aid in removing autoantibodies,
immune complexes, and cytotoxic constituents from serum and has been shown to
decrease recovery time by 50%. A review of 6 randomized controlled trials involving 649
participants found that plasma exchange helps speed recovery from GBS without causing
harm apart from being followed by a slightly increased risk of relapse.[91]
In well-controlled clinical trials, the efficacy of IVIGs in GBS patients has been shown to
equal that of plasma exchange.[92, 93, 94, 95] IVIG treatment is easier to implement and
potentially safer than plasma exchange, and the use of IVIGs versus plasma exchange
may be a choice of availability and convenience.
Immunotherapy for children with GBS has not been rigorously studied with randomized,
well-controlled studies, but is a standard aspect of treatment in this age group.[96]

Immunotherapy for pregnant women has not been studied, and safety for use during
pregnancy has not been established.
Corticosteroids (oral or IV) have not been found to have a clinical benefit.[97]
Consequently, this class of drugs is not currently employed in GBS treatment.
A few studies have investigated other medications to treat GBS; however, the trials have
been small and the evidence weak,[98] highlighting the need for further investigation of
potential treatment options.

Analgesia
Pain medications may be required in both the inpatient and outpatient settings. A tiered
pharmacologic approach that starts with nonsteroidal anti-inflammatory drugs or
acetaminophen, with narcotic agents added as needed, is usually recommended. Most
patients do not require narcotic analgesics after the first couple of months of illness.
Adjunct medications for pain, such as tricyclic antidepressants and certain
anticonvulsants, also may be beneficial for dysesthetic-type pains.

Consultations
Consultation with a neurologist can be helpful in the initial diagnosis, workup, and
treatment of patients admitted to the medical floor with GBS.
Critical care specialists may be required for patients in the ICU to help manage
respiratory failure and multiple medical complications.
Consultation with a pulmonologist may be needed to perform workup and to manage
respiratory issues, such as acute respiratory distress syndrome (ARDS), pneumonia, and
respiratory failure.
Consultation with a cardiologist may be required if significant cardiovascular
complications, such as labile blood pressure and cardiac arrhythmias, arise from the
associated autonomic dysfunction.
Consultation with a surgeon may be required for the placement of tracheostomies, enteral
feeding tubes, and central lines.
Physical medicine and rehabilitation specialists should evaluate patients for impairments
and disabilities arising from the disease and should help to determine the most
appropriate setting for and intensity of rehabilitation care.

Long-Term Monitoring

Although follow-up studies generally have assessed patients 6-12 months after onset,
some studies have reported continued improvements in strength even beyond 2 years.
With prolonged recovery possible, GBS patients with continued neurologic deficits may
benefit from ongoing physical therapy and conditioning programs.
Numerous papers have addressed the issue of persistent fatigue after recovery from GBS.
[87, 99, 100]
Studies have suggested that a large percentage of patients continue to have
fatigue-related problems, subsequently limiting their function at home, work, and during
leisure activities. Treatment suggestions range from gentle exercise to improvement in
sleep patterns to relief of pain or depression, if present. A study of amantadine found it no
more effective than placebo for relief of fatigue in GBS patients.[101]
GBS can produce long-lasting changes in the psychosocial status of patients and their
families.[73, 74, 75] Changes in work and leisure activities can be observed in just over one
third of these patients, and psychosocial functional health status can be impaired even
years after the GBS event.
Interestingly, psychosocial performance does not seem to correlate with the severity of
residual physical function. Poor conditioning and easy fatigability may be contributory
factors. Therefore, providing long-term attention and support for this population group is
important.

Medication Summary
Immunomodulatory therapy, such as plasmapheresis or the administration of intravenous
immunoglobulins (IVIGs), is frequently used in GBS patients.[102] The efficacy of
plasmapheresis and IVIGs appears to be about equal in shortening the average duration of
disease.[92, 93, 94, 95, 103] Combined treatment has not been shown to produce a further,
statistically significant reduction in disability.
The decision to use immunomodulatory therapy is based on the disease's severity and rate
of progression, as well as on the length of time between the condition's first symptom and
its presentation. Risks, such as thrombotic events associated with intravenous
immunoglobulin (IVIG), should be taken into consideration.[104, 105] Patients with severe,
rapidly progressive disease are most likely to benefit from treatment, with faster
functional recovery.[106