GUILLAIN-BARRE

SYNDROME

Dr. Saumya Mathur

Asst. Professor
Dept. of General Medicine
JNUIMSRC, Jaipur
 GUILLAIN-BARRE SYNDROME

• Guillain-Barre syndrome (GBS) is an acute, frequently severe, and

fulminant polyradiculoneuropathy that is autoimmune in nature.
•It occurs year-round at a rate of between 1 and 4 cases per
100,000 annually; in the United States, ~5000–6000 cases occur
per year.
•Males are at slightly higher risk for GBS than females.
•In Western countries, adults are more frequently affected than
children.
 Clinical Manifestations
GBS manifests as a rapidly evolving areflexic motor paralysis with
or without sensory disturbance. The usual pattern is an
ascending paralysis that may be first noticed as rubbery legs.
Weakness typically evolves over hours to a few days and is
frequently accompanied by tingling dysesthesia in the
extremities. The legs are usually more affected than the arms,
and facial diparesis is present in 50% of affected individuals.
The lower cranial nerves are also frequently involved, causing
bulbar weakness with difficulty handling secretions and
maintaining an airway. Pain in the neck, shoulder, back, or
diffusely over the spine is also common in the early stages of
GBS, occurring in ~50% of patients.
 Clinical Manifestations
Most patients require hospitalization, and in different series, up
to 30% require ventilatory assistance at some time during the
illness. Fever and constitutional symptoms are absent at the
onset and, if present, cast doubt on the diagnosis. Deep
tendon reflexes attenuate or disappear within the first few
days of onset. Cutaneous sensory deficits (e.g., loss of pain
and temperature sensation) are usually relatively mild, but
functions subserved by large sensory fibers, such as deep
tendon reflexes and proprioception, are more severely
affected.
 Clinical Manifestations
Bladder dysfunction may occur in severe cases but is usually
transient. If bladder dysfunction is a prominent feature and
comes early in the course, diagnostic possibilities other than
GBS should be considered, particularly spinal cord disease.
Once clinical worsening stops and the patient reaches a
plateau (almost always within 4 weeks of onset), further
progression is unlikely. Autonomic involvement is common.
The usual manifestations are loss of vasomotor control with
wide fluctuation in blood pressure, postural hypotension, and
cardiac arrhythmias. These features require close monitoring
and management and can be fatal.
 Types of GB Syndrome
Several subtypes of GBS are recognized, as determined primarily
by electrodiagnostic (Edx) and pathologic distinctions . The
most common variant is acute inflammatory demyelinating
polyneuropathy (AIDP). Additionally, there are two axonal
variants, which are often clinically severe—the acute motor
axonal neuropathy (AMAN) and acute motor sensory axonal
neuropathy (AMSAN) subtypes. In addition, a range of limited
or regional GBS syndromes are also encountered. Notable
among these is the Miller Fisher syndrome (MFS). It presents
as rapidly evolving ataxia and areflexia of limbs without
weakness, and ophthalmoplegia, often with pupillary
paralysis.
 Types of GB Syndrome
The MFS variant accounts for ~5% of all cases and is strongly
associated with antibodies to the ganglioside GQ1b . Other
regional variants of GBS include (1) pure sensory forms; (2)
ophthalmoplegia with anti-GQ1b antibodies as part of severe
motor-sensory GBS; (3) GBS with severe bulbar and facial
paralysis, sometimes associated with antecedent
cytomegalovirus (CMV) infection and anti-GM2 antibodies;
and (4) Acute Pandysautonomia .
 Antecedent Events
Approximately 70% of cases of GBS occur 1–3 weeks after an
acute infectious process, usually respiratory or
gastrointestinal. Culture and sero-epidemiologic techniques
show that 20–30% of all cases occurring in North America,
Europe, and Australia are preceded by infection or reinfection
with Campylobacter jejuni. A similar proportion is preceded
by a human herpes virus Infection, often CMV or Epstein-Barr
virus. Other viruses (e.g., HIV, hepatitis E) and also
Mycoplasma pneumoniae have been identified as agents
involved in antecedent infections, as have recent
immunizations.
 Antecedent Events
The swine flu vaccine, administered widely in the United States
in 1976, is the most notable example. Influenza vaccines in
use from 1992 to 1994, however, resulted in only one
additional case of GBS per million persons vaccinated, and the
more recent seasonal influenza vaccines appear to confer a
GBS risk of <1 per million. Epidemiologic studies looking at
H1N1 vaccination demonstrated at most only a slight
increased risk of GBS. Meningococcal vaccinations (Menactra)
does not appear to carry an increased risk.
 Antecedent Events
Older-type rabies vaccine, prepared in nervous system tissue, is
implicated as a trigger of GBS in developing countries where it
is still used; the mechanism is presumably immunization
against neural antigens. GBS also occurs more frequently than
can be attributed to chance alone in patients with lymphoma
(including Hodgkin’s disease), in HIV-seropositive individuals,
and in patients with systemic lupus erythematosus (SLE). C.
jejuni has also been implicated in summer outbreaks of AMAN
among children and young adults exposed to chickens in rural
China.
 Immunopathogenesis
Several lines of evidence support an autoimmune basis for acute
inflammatory demyelinating polyneuropathy (AIDP), the most
common and best-studied type of GBS; the concept extends
to all of the subtypes of GBS . It is likely that both cellular and
humoral immune mechanisms contribute to tissue damage in
AIDP. T cell activation is suggested by the finding that elevated
levels of cytokines and cytokine receptors are present in
serum (interleukin [IL] 2, soluble IL-2 receptor) and in
cerebrospinal fluid (CSF) (IL-6, tumor necrosis factor α,
interferon γ). AIDP is also closely analogous to an
experimental T cell–mediated immunopathy designated
experimental allergic neuritis (EAN).
 Immunopathogenesis
EAN is induced in laboratory animals by immune sensitization
against protein fragments derived from peripheral nerve
proteins, and in particular against the P2 protein. Based on
analogy to EAN, it was initially thought that AIDP was likely to
be primarily a T cell–mediated disorder; however, abundant
data now suggest that autoantibodies directed against non-
protein determinants may be central to many cases.
Circumstantial evidence suggests that all GBS results from
immune responses to nonself antigens (infectious agents,
vaccines) that misdirect to host nerve tissue through a
resemblance of epitope (molecular mimicry) mechanism . The
neural targets are likely to be glycoconjugates, specifically
gangliosides .
 Immunopathogenesis
Gangliosides are complex glycosphingolipids that contain one or
more sialic acid residues; various gangliosides participate in
cell-cell interactions (including those between axons and glia),
modulation of receptors, and regulation of growth. They are
typically exposed on the plasma membrane of cells, rendering
them susceptible to an antibody mediated attack.
Gangliosides and other glycoconjugates are present in large
quantity in human nervous tissues and in key sites, such as
nodes of Ranvier. Anti-ganglioside antibodies, most frequently
to GM1, are common in GBS (20–50% of cases), particularly in
AMAN and AMSAN and in those cases preceded by C. jejuni
infection.
 Immunopathogenesis
Furthermore, isolates of C. jejuni from stool cultures of patients
with GBS have surface glycolipid structures that antigenically
cross react with gangliosides, including GM1, concentrated in
human nerves. Sialic acid residues from pathogenic C. jejuni
strains can also trigger activation of dendritic cells via
signaling through a toll-like receptor (TLR4), Promoting B cell
differentiation and further amplifying humoral autoimmunity.
Another line of evidence is derived from experience in Europe
with parenteral use of purified bovine brain gangliosides for
treatment of various neuropathic disorders. Between 5 and 15
days after injection, some recipients developed acute motor
axonal GBS with high titers of anti-GM1 antibodies that
recognized epitopes at nodes of Ranvier and motor endplates.
 Immunopathogenesis
Experimentally, anti-GM1 antibodies can trigger complement-
mediated injury at paranodal axon-glial junctions, disrupting
the clustering of sodium channels and likely contributing to
conduction block Anti-GQ1b IgG antibodies are found in >90%
of patients with MFS and titers of IgG are highest early in the
course. Anti-GQ1b antibodies are not found in other forms of
GBS unless there is extraocular motor nerve involvement. A
possible explanation for this association is that extraocular
motor nerves are enriched in GQ1b gangliosides in
comparison to limb nerves. In addition, a monoclonal anti-
GQ1b antibody raised against C. jejuni isolated from a patient
with MFS blocked neuromuscular transmission
experimentally.
 Immunopathogenesis
Taken together, these observations provide strong but still
inconclusive evidence that autoantibodies play an important
pathogenic role in GBS. Although antiganglioside antibodies
have been studied most intensively, other antigenic targets
may also be important. One report identified IgG antibodies
against Schwann cells and neurons (nerve growth cone
region) in some GBS cases. Proof that these antibodies are
pathogenic requires that they be capable of mediating
disease. Following direct passive transfer to naive hosts; this
has not yet been demonstrated, although one case of possible
maternal-fetal transplacental transfer of GBS has been
described.
 Immunopathogenesis
In AIDP, an early step in the induction of tissue damage appears
to be complement deposition along the outer surface of the
Schwann cell. Activation of complement initiates a
characteristic vesicular disintegration of the myelin sheath
and also leads to recruitment of activated macrophages,
which participate in damage to myelin and axons. In AMAN,
the pattern is different in that complement is deposited along
with IgG at the nodes of Ranvier along large motor axons.
Interestingly, in cases of AMAN, antibodies against GD1a
appear to have a fine specificity that favors binding to motor
rather than sensory nerve roots, even though this ganglioside
is expressed on both fiber types.
 Pathophysiology
In the demyelinating forms of GBS, the basis for flaccid paralysis
and sensory disturbance is conduction block. This finding,
demonstrable electrophysiologically, implies that the axonal
connections remain intact. Hence, recovery can take place
rapidly as remyelination occurs. In severe cases of
demyelinating GBS, secondary axonal degeneration usually
occurs; its extent can be estimated electrophysiologically.
More secondary axonal degeneration correlates with a slower
rate of recovery and a greater degree of residual disability.
 Pathophysiology
When a severe primary axonal pattern is encountered
electrophysiologically, the implication is that axons have
degenerated and become disconnected from their targets,
specifically the neuromuscular junctions, and must therefore
regenerate for recovery to take place. In motor axonal cases in
which recovery is rapid, the lesion is thought to be localized to
preterminal motor branches, allowing regeneration and
reinnervation to take place quickly. Alternatively, in mild
cases,collateral sprouting and reinnervation from surviving
motor axons near the neuromuscular junction may begin to
reestablish physiologic continuity with muscle cells over a
period of several months.
 Laboratory Features
CSF findings are distinctive, consisting of an elevated CSF protein
level (1–10 g/L [100–1000 mg/dL]) without accompanying
pleocytosis. The CSF is often normal when symptoms have
been present for ≤48 h; by the end of the first week, the level
of protein is usually elevated. A transient increase in the CSF
white cell count (10–100/μL) occurs on occasion in otherwise
typical GBS; however, a sustained CSF pleocytosis suggests an
alternative diagnosis (viral myelitis) or a concurrent diagnosis
such as unrecognized HIV infection, leukemia or lymphoma
with infiltration of nerves, or neurosarcoidosis.
 Laboratory Features
Electrodiagnostic features are mild or absent in the early stages
of GBS and lag behind the clinical evolution. In AIDP, the
earliest features are prolonged F-wave latencies, prolonged
distal latencies, and reduced amplitudes of compound muscle
action potentials (CMAPs), probably owing to the predilection
for involvement of nerve roots and distal motor nerve
terminals early in the course. Later, slowing of conduction
velocity, conduction block, and temporal dispersion may be
appreciated .
 Laboratory Features
Occasionally, sensory nerve action potentials (SNAPs) may be
normal in the feet (e.g., sural nerve) when abnormal in the
arms. This is also a sign that the patient does not have one of
the more typical “length-dependent” polyneuropathies. In
cases with primary axonal pathology, the principal Edx finding
is reduced amplitude of CMAPs (and also SNAPS with AMSAN)
without conduction slowing or prolongation of distal
latencies.
 Diagnosis
The diagnosis of AIDP is made by recognizing the pattern of
rapidly evolving paralysis with areflexia, absence of fever or
other systemic symptoms, and characteristic antecedent
events.
 Differential Diagnosis
It includes acute myelopathies (especially with prolonged back
pain and sphincter disturbances); diphtheria (early
oropharyngeal disturbances); Lyme polyradiculitis and other
tick-borne paralyses; porphyria (abdominal pain, seizures,
psychosis); vasculitic neuropathy (raised ESR ) ; poliomyelitis
(fever and meningismus common); West Nile virus; CMV
polyradiculitis (in immunocompromised patients); critical
illness neuropathy or myopathy; neuromuscular junction
disorders such as myasthenia gravis and botulism (pupillary
reactivity lost early); poisonings with organophosphates,
thallium, or arsenic; paralytic shellfish poisoning; or severe
hypophosphatemia (rare).
Laboratory tests are helpful primarily to exclude mimics of GBS.
Edx features may be minimal, and the CSF protein level may
not rise until the end of the first week. If the diagnosis is
strongly suspected, treatment should be initiated without
waiting for evolution of the characteristic Edx and CSF findings
to occur. GBS patients with risk factors for HIV or with CSF
pleocytosis should have a serologic test for HIV.
 Treatment of Guillain-Barré Syndrome
In the vast majority of patients with GBS, treatment should be
initiated as soon after diagnosis as possible. Each day counts; ~2
weeks after the first motor symptoms, it is not known whether
immunotherapy is still effective. If the patient has already
reached the plateau stage, then treatment probably is no longer
indicated, unless the patient has severe motor weakness and
one cannot exclude the possibility that an immunologic attack is
still ongoing. Either high-dose intravenous immune globulin
(IVIg) or plasmapheresis can be initiated, as they are equally
effective for typical GBS. A combination of the two therapies is
not significantly better than either alone. IVIg is often the initial
therapy chosen because of its ease of administration and good
safety record.
 Treatment
Anecdotal data have also suggested that IVIg may be preferable
to plasma exchange (PE) for the AMAN and MFS variants of
GBS. IVIg is administered as five daily infusions for a total dose
of 2 g/kg body weight. A course of plasmapheresis usually
consists of ~40–50 mL/kg PE four to five times over a week.
Meta-analysis of randomized clinical trials indicates that
treatment reduces the need for mechanical ventilation by
nearly half (from 27% to 14% with PE) and increases the
likelihood of full recovery at 1 year (from 55% to 68%).
 Treatment
Functionally significant improvement may occur toward the end
of the first week of treatment or may be delayed for several
weeks. The lack of noticeable improvement following a course
of IVIg or PE is not an indication to treat with the alternate
treatment. However, there are occasional patients who are
treated early in the course of GBS and improve, who then
relapse within a month. Brief retreatment with the original
therapy is usually effective in such cases. Glucocorticoids have
not been found to be effective in GBS. Occasional patients
with very mild forms of GBS, especially those who appear to
have already reached a plateau when initially seen, may be
managed conservatively without IVIg or PE.
 Treatment
In the worsening phase of GBS, most patients require monitoring
in a critical care setting, with particular attention to vital
capacity, heart rhythm, blood pressure, nutrition, deep vein
thrombosis prophylaxis, cardiovascular status, early
consideration (after 2 weeks of intubation) of tracheotomy,
and chest physiotherapy. As noted, ~30% of patients with GBS
require ventilatory assistance, sometimes for prolonged
periods of time (several weeks or longer). Frequent turning
and assiduous skin care are important, as are daily range of
motion exercises to avoid joint contractures and daily
reassurance as to the generally good outlook for recovery.
 Prognosis and Recovery
Approximately 85% of patients with GBS achieve a full functional
recovery within several months to a year, although minor
findings on examination (such as areflexia) may persist and
patients often complain of continued symptoms, including
fatigue. The mortality rate is <5% in optimal settings; death
usually results from secondary pulmonary complications. The
outlook is worst in patients with severe proximal motor and
sensory axonal damage. Such axonal damage may be either
primary or secondary in nature , but in either case successful
regeneration cannot occur. Other factors that worsen the
outlook for recovery are advanced age, a fulminant or severe
attack, and a delay in the onset of treatment.
 Chronic Inflammatory Demyelinating
Polyneuropathy (CIDP)
CIDP is distinguished from GBS by its chronic course. In other
respects, this neuropathy shares many features with the
common demyelinating form of GBS, including elevated CSF
protein levels and the Edx findings of acquired demyelination.
Most cases occur in adults, and males are affected slightly
more often than females. The incidence of CIDP is lower than
that of GBS, but due to the protracted course, the prevalence
is greater.
 Clinical Manifestations
Onset is usually gradual over a few months or longer, but in a few
cases, the initial attack is indistinguishable from that of GBS. An
acute-onset form of CIDP should be considered when GBS
deteriorates >9 weeks after onset or relapses at least three
times. Symptoms are both motor and sensory in most cases.
Weakness of the limbs is usually symmetric but can be strikingly
asymmetric in multifocal acquired demyelinating sensory and
motor (MADSAM) neuropathy variant (Lewis-Sumner syndrome)
in which discrete peripheral nerves are involved. There is
considerable variability from case to case. Some patients
experience a chronic progressive course, whereas others, usually
younger patients, have a relapsing and remitting course.
Some have only motor findings, and a small proportion present
with a relatively pure syndrome of sensory ataxia. Tremor
occurs in ~10% and may become more prominent during
periods of subacute worsening or improvement. A small
proportion have cranial nerve findings, including external
ophthalmoplegia. CIDP tends to ameliorate over time with
treatment; the result is that many years after onset, nearly
75% of patients have reasonable functional status. Death from
CIDP is uncommon.
 Diagnosis
The diagnosis rests on characteristic clinical, CSF, and
electrophysiologic findings. The CSF is usually acellular with
an elevated protein level, sometimes several times normal. As
with GBS, a CSF pleocytosis should lead to the consideration
of HIV infection, leukemia or lymphoma, and
neurosarcoidosis. Edx findings reveal variable degrees of
conduction slowing, prolonged distal latencies, distal and
temporal dispersion of CMAPs, and conduction block as the
principal features. In particular, the presence of conduction
block is a certain sign of an acquired demyelinating process.
Evidence of axonal loss, presumably secondary to
demyelination, is present in >50% of patients.
Serum protein electrophoresis with immunofixation is indicated
to search for monoclonal gammopathy and associated
conditions. In all patients with presumptive CIDP, it is also
reasonable to exclude vasculitis, collagen vascular disease
(especially SLE), chronic hepatitis, HIV infection, amyloidosis,
and diabetes mellitus. Other associated conditions include
inflammatory bowel disease and lymphoma.
 Pathogenesis
Although there is evidence of immune activation in CIDP, the
precise mechanisms of pathogenesis are unknown. Biopsy
typically reveals little inflammation and onion-bulb changes
(imbricated layers of attenuated Schwann cell processes
surrounding an axon) that result from recurrent
demyelination and remyelination . The response to therapy
suggests that CIDP is immune-mediated; CIDP responds to
glucocorticoids, whereas GBS does not.
Passive transfer of demyelination into experimental animals has
been accomplished using IgG purified from the serum of some
patients with CIDP, lending support for a humoral
autoimmune pathogenesis. A minority of patients have
serum antibodies against P0, myelin P2 protein, PMP22, or
neurofascin. It is also of interest that a CIDP-like illness
developed spontaneously in the nonobese diabetic (NOD)
mouse when the immune co-stimulatory molecule B7-2
(CD86) was genetically deleted; this suggests that CIDP can
result from altered triggering of T cells by antigen presenting
cells.
Approximately 25% of patients with clinical features of CIDP also
have a monoclonal gammopathy of undetermined significance
(MGUS). Cases associated with monoclonal IgA or IgG kappa
usually respond to treatment as favorably as cases without a
monoclonal gammopathy. Patients with IgM monoclonal
gammopathy and antibodies directed against myelin-
associated glycoprotein (MAG) have a distinct
polyneuropathy, tend to have more sensory findings and a
more protracted course, and usually have a less satisfactory
response to treatment.
 Treatment of CIDP
Most authorities initiate treatment for CIDP when progression is
rapid or walking is compromised. If the disorder is mild,
management can be expectant, awaiting spontaneous
remission. Controlled studies have shown that high-dose IVIg,
PE, and glucocorticoids are all more effective than placebo.
Initial therapy is usually with IVIg, administered as 2.0 g/kg
body weight given in divided doses over 2–5 days; three
monthly courses are generally recommended before
concluding a patient is a treatment failure. If the patient
responds, the infusion intervals can be gradually increased or
the dosage decreased (e.g., 1 g/kg per month).
PE, which appears to be as effective as IVIg, is initiated at two to
three treatments per week for 6 weeks; periodic re-treatment
may also be required. Treatment with glucocorticoids is
another option (60–80 mg prednisone PO daily for 1–2
months, followed by a gradual dose reduction of 10 mg per
month as tolerated), but long-term adverse effects including
bone demineralization, gastrointestinal bleeding, and
cushingoid changes are problematic. As many as one-third of
patients with CIDP fail to respond adequately to the initial
therapy chosen; a different treatment should then be tried.
Patients who fail therapy with IVIg, PE, and glucocorticoids may
benefit from treatment with immunosuppressive agents such
as azathioprine, methotrexate, cyclosporine, and
cyclophosphamide, either alone or as adjunctive therapy.
Early experience with anti-CD20 (rituximab) has also shown
promise. Use of these therapies requires periodic
reassessment of their risks and benefits. In patients with a
CIDP-like neuropathy who fail to respond to treatment, it is
important to evaluate for POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy,
skin changes) .
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