International Journal of Neuroscience, 2014; 00(00): 1–6

Copyright © 2014 Informa Healthcare USA, Inc.

ISSN: 0020-7454 print / 1543-5245 online
DOI: 10.3109/00207454.2014.913588

REVIEW

Pathophysiology and diagnosis of Guillain–Barré

syndrome – challenges and needs
Sambit Dash,1 Aparna R. Pai,2 Ullas Kamath,1 and Pragna Rao3
1
Department of Biochemistry, Melaka Manipal Medical College (Manipal Campus); 2 Department of Neurology, Kasturba
Hospital, Manipal, Manipal University; 3 Department of Biochemistry, Kasturba Medical College, India, Manipal
University, Manipal, Karnataka, India

Guillain–Barré syndrome (GBS) is an autoimmune polyneuropathy which presents with acute onset and rapid
progression of flaccid, hyporeflexi quadriparesis. Both sensory and autonomic nerve involvement is seen. GBS
has various subtypes that vary in their pathophysiology. The pathogenesis involves an immune response trig-
gered by a preceding event which may be an infection, immunisation or surgical procedure. Clinical diagnosis
has been largely the primary diagnosing criterion for GBS along with electrodiagnosis, which has several pit-
falls and is supported by ancillary testing of cerebrospinal fluid (CSF) analysis and Nerve Conduction Studies.
Measurement of anti-ganglioside antibodies is also an effective tool in its diagnosis. Further understanding of
pathophysiology and better diagnostic methods are required for better management of GBS.
KEYWORDS: autoimmunity, molecular mimicry, Campylobacter jejuni, anti-ganglioside antibodies, electrodiagnosis

Introduction and could lead to an ascending paralysis. Legs become

weak and the paralysis then sets in the upper limbs and
French neurologists Georges Guillain, Jean-Alexandre the face. During this time, there is usually a complete
Barré and André Strohl, in the year 1916, observed loss of deep tendon reflexes [6–8].
acute areflexic paralysis in two individuals which recov- Infections with a number of bacteria and viruses are
ered with time. They found an increased protein con- linked to the onset of GBS, of which the most common
centration in the cerebrospinal fluid [1–3]. Called as is the gram negative diarrhea causing bacteria, Campy-
Guillain–Barré syndrome (GBS), it was described as a lobacter jejuni. Autoimmunity which has been a mainstay
clinical condition characterised by rapid spread of as- in the pathogenesis of GBS involves in it various mecha-
cending upper or lower limb weakness, defective tendon nisms depending on the sub-types of GBS. Greater un-
reflexes, weak sensory signs and possible autonomic dys- derstanding of these pathogenesis mechanisms will help
functions. In the western countries, post-polio eradica- in developing countering strategies. Another area that
tion, GBS is a prominent cause of acute flaccid paral- needs focus is the diagnostic aspect. While presently
ysis, bearing resemblance with poliomyelitis and many the widely used electrodiagnostic testing is unspecific at
other non-specific conditions like AIDS post-surgery, times; an accurate diagnosis and especially early in the
etc. [4,5]. Inflammation of peripheral nerves, to a larger course of the syndrome can help check this often life
extent, causes GBS. Sensory information like pain, tem- threatening syndrome.
perature is conveyed from the body to the brain and mo-
tor signals like movements, etc., are conveyed from the
Epidemiology
brain to the body by these nerves. A tingling sensation
in the legs and arms is felt in GBS. This could be severe The incidence of GBS is 0.6 to 4 cases per 100,000 pop-
ulation per year across the world [9]. It occurs at all
Received 10 February 2014; revised 21 March 2014; accepted 7 April 2014.
ages with peaks at adolescence and old age. Below age
40, at an incidence rate of yearly 1.3–1.9 per 100,000
Correspondence: Sambit Dash, MSc, Department of Biochemistry, Melaka population, the incidence rate remains unvarying. Stud-
Manipal Medical College, Manipal University, Madhavnagar, Manipal,
Karnataka 576104, India. Tel: +91-820-2922519. ies show a slight increase in incidence during late ado-
E-mail: [email protected] lescence and young adulthood. Increased infection risk

1
2 S. Dash et al.

with Cytomegalovirus (CMV) and Campylobacter jejuni AMAN, the neurological deficit is purely motor [29,30].
at that age and in the elderly stands as the reason for the Rare cases of acute transient sensory neuropathy may
peaks of incidence [10–12]. There is consensus that men represent AIDP affecting only sensory nerves or roots
are predisposed to GBS 1·5 times more than women. but need to be distinguished from acute sensory neu-
Europe and North America see a steady rise in inci- ronopathy. Autonomic involvement is common in GBS,
dence rate in advancing age [13]. Some types of im- especially in severe cases with respiratory failure. Some
munisations have also been reported to trigger GBS in cases of acute dysautonomia without involvement of so-
susceptible persons. Post “swine flu” vaccination in the matic nerves may be inflammatory and possibly autoim-
USA in 1976, slight increase in GBS incidence rates oc- mune. In most cases, the nerve supply of the limb, cra-
curred [14–16]. Rabies vaccine containing brain mate- nial and respiratory muscles is diffusely and symmet-
rial is seen to cause GBS at a rate of one in 1000 cases rically affected; in a minority, the neurological deficit
[17,18]. The lifetime likelihood of any individual acquir- is much more focused. The most frequent example of
ing GBS is projected at 1 in 1000 [19]. the latter is the Fisher syndrome consisting of ophthal-
moplegia, ataxia and areflexia with variable degrees of
bulbar muscle involvement [31]. Some patients resem-
Preceding events
ble this syndrome at the onset and then develop gen-
The relation of preceding illness was not studied by neu- eralised weakness, FS/GBS overlap syndrome. There is
rologists who defined GBS, namely Guillain, Barré and also a rare group that develops bulbar involvement, some
Strohl. However, a wide range of clinical observations of whom also develop upper limb involvement. Most
aided by epidemiological studies, establish that about patients with GBS have a monophasic disease. Recur-
75% of patients report preceding infection as history. rences occur in less than 3% of patients. Such patients
GBS thus could be called a post-infectious illness. The and those whose illness has a protracted onset phase may
patients report an antecedent infection which is acute be difficult to distinguish from chronic inflammatory de-
and which commonly involves respiratory-tract or gas- myelinating polyradiculoneuropathy (CIDP). There is
trointestinal tract. The infection subsides by the time the likely to be a spectrum from acute through subacute
neuropathic symptoms starts. The time taken for GBS to chronic inflammatory demyelinating polyneuropathy,
to set in after the preceding infection varies between reflecting the fact that these illnesses share some patho-
one and three weeks and sometimes longer. In several genetic mechanisms [32] (Tables 1 and 2).
large studies, the average was 11 days [20]. When cul-
ture studies were done in the serum of patients, about
Pathogenesis
30% to 50% of cases were found to have antecedent in-
fections [21]. Campylobacter jejuni, a prominent bacteria The GBS is considered to be an immune-mediated
causing gastroenteritis worldwide, has been identified as polyneuropathy since in the peripheral nerves of these
the organism widely associated with GBS. This link has patients, deposits of complement, immunoglobulins,
been recorded in many studies and in 14 large prospec- and infiltration of macrophages are seen. In the
tive studies. C jejuni culture studies have reflected that blood of GBS patients, anti-ganglioside antibodies,
the infection causing GBS ranged from 26% to 41%
in a series of isolated GBS cases from countries like
the UK, the Netherlands, the USA, and Japan [22–25]. Table 1. Distribution of gangliosides in peripheral nervous
Case-controlled studies show a significant association of system [59].
GBS with not only C jejuni, but also CMV, and probably Target antigens
Epstein–Barr (EPB) virus [26,27]. of anti-ganglioside
antibodies Localisation in human PNS

Variants GM1 Not determined. In animals axolemma

at node and paranode, dorsal root
Individual patients with GBS may be classified accord- ganglia (DRG)
ing to whether the myelin sheaths or axons are pri- GM1b Not determined
marily affected and whether the motor, sensory or au- GD1a Motor nerve terminal
GalNac GD 1a Periaxonal membrane of motor nerve at
tonomic systems are involved. In North America and node and paranode, axolemma of
Europe, typical patients with GBS usually have AIDP small fibers in sural nerve
as the underlying subtype, and only about 5% of the GD1b Large neurons in DRG, paranodal
patients have axonal subtypes of the disease [28]. In myelin
northern China, Japan and Central and South America, GQ1b Paranodal myelin of oculomotor,
trovhlear, and abducens nerves
axonal forms are more common [29,30]. In AMSAN, GT1a Not determined
sensory axons and motor neurons are affected [31]. In

International Journal of Neuroscience

 Challenges and Needs 3

Table 2. Classification of GBS and related disorders and typical A, which anchors the molecule in outer bacterial mem-
antiganglioside antibodies by Hughes and Cornblath [3]. brane and a core oligosaccharide and a polymer of re-
Acute inflammatory peating oligosaccharides. LPS of C jejuni strain contains
demyelinating in its core oligosaccharide, sialic acids which are charac-
polyneuropathy (AIDP) Not known teristics for gangliosides [42,43].
Anti-ganglioside antibodies also play a role in patho-
Acute motor and sensory axonal GM1, GM1b, GD1a
neuropathy (AMSAN) genesis of GBS. They usually mediate the disease pro-
Acute motor axonal neuropathy GM1, GM1b, GD1a, gression by complement dependent action. In AMAN,
(AMAN) GalNac GD 1a autopsy studies have shown IgG and complement de-
Acute sensory ataxic neuropathy GD1b posits on axolemma at the nodes of Ranvier of mo-
Fisher’s syndrome GQ1b, GT1a
tor fibers. Demyelination and lymphatic infiltration is
minimal which is followed by macrophage infiltration.
C jejuni bound to motor nerve terminals destruct neu-
inflammatory cytokines and activated T-cells are also romuscular junction in a complement dependent man-
found [33,34]. In 1982, lIyas et al. first reported that ner in AMAN. In Miller Fischer syndrome too by clas-
antibodies to gangliosides in serum from a subgroup of sic complement pathway activation, which forms pores
GBS patients were present [35]. Gangliosides are sia- on membrane attack in presynaptic membrane causing
lylated glycosphingolipids which differ from each other neuronal and perisynaptic Schwann cell injury. Thus,
with respect to the oligosaccharide attached. Ganglio- complement inhibitors are also being tried for therapeu-
sides are found in relatively high concentrations in neu- tic uses [59].
ral membranes. Their role possibly is in multiple signal
recognition processes [36,37]. Specific gangliosides are
Diagnosis
distributed typically in peripheral nerves; GM1 is con-
centrated in axons, and in myelin of motor nerve fibres, Early diagnosis of GBS is essential as early treatment
while GQ1b is majorly found in myelin of oculomotor decreases the duration of GBS and its severity. It would
nerves [38–40]. The concept of molecular mimicry as also help in reducing GBS patients that would require
a possible mechanism via which infections may induce mechanical ventilation. Confirmation of diagnosis of
pathogenic immune responses, has been proposed in GBS depends on Nerve Conduction Studies (NCS). It
many autoimmune diseases [41,42]. The role of molec- along with electromyography (EMG) are used in diag-
ular mimicry between microbial and autologous anti- nosis, and different neurophysiological diagnostic crite-
gens in producing a cross-reactive immune response can ria have been proposed [39]. NCS serves in differential
be established at different levels: (i) homology in bio- diagnosis, to find out the subtype of GBS and to exclude
chemical structure or linear amino acid sequence, (ii) other mimics. NCS is based on abnormalities in motor
cross-reactivity of antibodies with both structures, (iii) nerves in order to characterise demyelination; sensory
cross-reactive antibodies could be induced by process nerve conduction studies help to classify axonal GBS
of immunisation with the microbial antigen and (iv) in- into AMAN and AMSAN. The ability of NCS to diag-
duction of cross-reactive antibodies which induce dys- nose better is enhanced by studying a minimum of three
function or tissue damage [42,43]. sensory and four motor nerves. F-waves and H reflexes
For a cross-reactive immune response to be initiated may also be studied additionally [40,41].
against autologous antigens, by the process of molecu- Clinical diagnostic criteria of GBS have been set but
lar mimicry, two primary events need to occur. The first no such neurophysiological criteria for classification has
being similarity between the microbial and the autolo- been set [28,42–45]. Electrodiagnostic studies help in
gous antigen so that immune responses can cross-react. the evaluation of patients by helping in diagnosis, classi-
The second requirement being sufficient dissimilarity of fication and establishing prognosis [28, 46,47]. Abnor-
the microbial antigen from the autologous antigen. This mal late responses are most common findings in elec-
is required so that the immune systems tolerance to self trodiagnostic studies within 10 days of setting of GBS
is broken and a very specific immune response is gen- [48,49]. Distal temporal dispersion (TD) [50], partial
erated. This could occur by affinity maturation of iso- motor conduction block (CB) [51], abnormal blink re-
type switch processes. Lipopolysaccharide (LPS) found flex (BR) [52,50], the presence of multiple A-waves
in cell walls of C jejuni strains have been found to in- [53], and a sural-sparing pattern could be used as neu-
duce anti-ganglioside antibodies in some patients. LPS rophysiological markers.
are cell wall components of most gram-negative bac- Electrodiagnostic findings may not meet neurophys-
teria. The LPS structure talks for it being responsible iologic criteria in the early stages of GBS [50,54,55].
for molecular mimicry. It consists of primarily a lipid It though could be said that neurophysiological tests


C 2014 Informa Healthcare USA, Inc.
4 S. Dash et al.

Table 3. Suggested investigations for Guillain–Barré syndrome Table 4. Differential diagnosis of GBS as described by Hughes
as proposed by Hughes and Cornblath[3]. and Cornblath [3].

Studies to establish diagnosis of GBS: Differential diagnosis of GBS:

Following are the list of possible causes overlapping
Electrodiagnostic studies GBS presentation and needs to be ruled out
CSF analysis
Studies in special circumstances: 1. Brainstem encephalitis
Urine porphobilinogen and delta amino levulinic acid 2. Brainstem stroke
HIV testing 3. Peripheral neuropathy
Drug and toxin testing • Guillain–Barré syndromes
Studies to understand the causation: • Post-rabies vaccine neuropathy
Stool culture and serology for C jejuni • Diphtheritic neuropathy
Stool culture for poliovirus • Heavy metals, biological toxins or drug intoxication
M pneumonia • Acute intermittent porphyria
Antibodies to gangliosides • Vasculitic neuropathy
CMV, EPB virus serology • Critical illness neuropathy
• Lymphomatous neuropathy
4. Disorders of muscle
• Hypokalaemia
• Hypophosphataemia
do not remain completely normal in GBS, but it could • Inflammatory myopathy
• Acute rhabdomyolysis
be a possibility. This could be because demyelina- • Trichinosis
tion has occurred but at those sites which are very • Periodic paralyses
proximal, making electrodiagnostic testing difficult [56]. 5. Acute anterior poliomyelitis
Increased cerebrospinal fluid (CSF) protein concentra- • Caused by poliovirus
tion is non-specific and is present in more than two- • Caused by other neurotropic viruses
6. Disorders of neuromuscular transmission
thirds of patients, the protein content tends to remain • Myasthenia gravis
normal in early stages of GBS [57] (Table 3). • Biological or industrial toxins
7. Acute myelopathy
• Space-occupying lesions
• Acute transverse myelitis
Challenges in diagnosis

Differential diagnosis – overlaps

A wide range of disorders have overlapped with clinical of different NCS criteria which ranged from 39.2% to
symptoms of GBS and thus have to be carefully ruled 88.2% in an Indian population [58,59].
out while diagnosing GBS. The fact that a physician
might encounter rarely cases of GBS in his or her life-
Biochemical screening
time adds to the complexity of diagnosis (Table 4).
CSF and serum analysis are carried out as ancillary
testing in GBS. CSF protein rises in more than three-
Electrodiagnosis
fourths of patients, with mononuclear cell count which
Uncini et al. [53]describe the pitfall in diagnosis of GBS might be normal or abnormal. However, it remains nor-
with relation to electrodiagnosis; axonal GBS is patho- mal in the initial days of disease setting in. Analysis
physiologically characterised not only by axonal degen- for anti-nuclear antibodies, extractable nuclear antibod-
eration but also by reversible conduction failure at the ies, anti-neutrophil cytoplasmic antibodies, erythrocyte
axolemma of the node of Ranvier. The lack of differ- sedimentation rate, C-reactive protein, electrolyte, urea,
ence among blocks of conduction due to demyelination, creatinine levels, blood sugar levels and serum delta-
failure of reversible conduction and compound muscle aminolevulinic acid for porphyria are carried out but are
action trigger potential amplitude reduction depending non-specific. Urine porphobilinogen is also sometimes
on length and may falsely diagnose patients with axonal estimated [8].
GBS as having AIDP. A series of electrophysiological
studies is required for diagnosis of GBS subtypes accu-
The road ahead
rately and for the understanding of pathophysiological
mechanisms of muscle weakness. Trustworthy electro- The inflammatory pathways involving a host of cy-
diagnostic criteria which take into account the reversible tokines and other molecules, both pro- and anti-
conduction failure pattern should evolve [47]. Another inflammatory, and their interplay, suggests the complex-
study by Kalita et. al. presents variations in sensitivity ity in the disease progress and recovery. The various

International Journal of Neuroscience

 Challenges and Needs 5

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