Guillain-Barré Syndrome

and Related Disorders 28

Ezequiel Agustin Piccione, Karim Salame,
and Bashar Katirji

Table 28.1 Diagnostic features of the typical form of Guillain-Barré

Introduction syndrome, acute inflammatory demyelinating polyradiculoneuropathy
(AIDP)
Guillain-Barré syndrome (GBS), also known as
Clinical features
Landry-Guillain-Barré-Strohl syndrome, was described in
Required for the diagnosis:
1916 [1, 2]. GBS is usually a predominantly motor disorder Progressive weakness in both arms and legs
with areflexia and subjective more than objective sensory Areflexia or hyporeflexia (generalized or in weak limbs)
symptoms. GBS is the most common cause of acute flaccid Strongly supporting the diagnosis:
paralysis worldwide, particularly with the almost complete Progression of symptoms over days to 4 weeks
eradication of poliomyelitis. Its incidence in North America Relative symmetry of symptoms
and Europe ranges from 0.8 to 1.9 cases per 100,000 popula- Mild sensory symptoms or signs
tion. GBS affects individuals of all races and ages, but is more Cranial nerve involvement, especially facial diplegia
common in subjects above 50-year-old [3, 4], and the inci- Recovery beginning 2–4 weeks after progression ceases
dence increases by 20 % for every 10-year increase in age [5]. Autonomic dysfunction
The annual incidence of GBS increased with age from A preceding upper respiratory or gastrointestinal illness
1.7/100,000 before 50 years to 3.3/100,000 after 50 years. The Absence of fever at the outset
annual incidence in children less than 15 years old is between Making the diagnosis doubtful:
0.34 and 1.34 per 100,000 population [4]. GBS affects males Well-demarcated sensory level
Marked, persistent asymmetry of symptoms or signs
more than females with a male to female ratio of 1.78.
Severe and persistent bladder or bowel dysfunction
For many years since its original description, GBS was
Excluding the diagnosis:
considered to be a single disorder and interchangeably named
Diagnosis of botulism, myasthenia gravis, poliomyelitis, or toxic
acute inflammatory demyelinating polyradiculoneuropathy neuropathy
(AIDP), based on evidence of acute immune attack on myelin Abnormal porphyrin metabolism
and resemblance to experimental allergic neuritis. In addition, Recent diphtheria
criteria for the published diagnosis of GBS have been based on Meningeal carcinomatosis or lymphomatosis
AIDP clinical and electrophysiological features (Table 28.1). Laboratory criteria
Elevated CSF protein concentration with no pleocytosis or fewer
than 10 cell/mm3
Electrophysiological criteria (any 3 of 4 criteria)
E.A. Piccione, MD (*) • K. Salame, MD
Reduction in conduction velocity of 2 or more motor nerves
Department of Neurology,
<80 % lower limit of normal (LLN) if amplitude >80 % of LLN;
The Neurological Institute, University Hospitals Case Medical Center
<70 % of LLN if amplitude <80 % of LLN
and Case Western Reserve University School of Medicine,
11100 Euclid Avenue, Cleveland, OH 44106, USA Prolonged distal latencies in 2 or more motor nerves >125 % of
e-mail: [email protected] the upper limit of normal (ULN) if amplitude >80 % of LLN;
>150 % of ULN if amplitude <80 %
B. Katirji, MD, FACP Absent or prolonged minimum F-waves in 2 or more motor
Neuromuscular Center & EMG Laboratory, nerves, >120 % of ULN if amplitude >80 % of LLN; >150 % of
Department of Neurology, The Neurological Institute, ULN if amplitude is <80 % of LLN
University Hospitals Case Medical Center and
Conduction block or abnormal temporal dispersion (>20 % drop
Case Western Reserve University School of Medicine,
in amplitude or >15 % change in duration between proximal and
11100 Euclid Avenue, Bolwell Building, 5th Floor,
distal sites) in 1 or more motor nerves
Cleveland, OH, 44106, USA
e-mail: [email protected] Adapted with revisions from Asbury and Cornblath [6], pp 521–524

B. Katirji et al. (eds.), Neuromuscular Disorders in Clinical Practice, 573

DOI 10.1007/978-1-4614-6567-6_28, © Springer Science+Business Media New York 2014
574 E.A. Piccione et al.

Table 28.2 Classification of Guillain-Barré syndrome Table 28.3 Antecedent illnesses associated with Guillain-Barré
syndrome
GBS types
Acute inflammatory demyelinating polyradiculoneuropathy Viral infections
(AIDP) Cytomegalovirus
Acute motor-sensory axonal neuropathy (AMSAN) Influenza
Acute motor axonal neuropathy (AMAN) Parainfluenza
GBS variants Epstein-Barr virus
Miller Fisher syndrome Cocksackie
Ataxic variant (acute ataxic neuropathy) Echo
Pharyngeal-cervical-brachial variant Measles
Multiple cranial neuropathy variant Mumps
Facial diplegia with paresthesias Rubella
Paraparetic variant Herpes simplex virus
Acute pandysautonomia (acute autonomic neuropathy) Herpes Zoster virus
Others Hepatitis A and B virus
Human immunodeficiency virus
Bacterial and other infections
More recently, it has become clear that AIDP represent only Campylobacter jejuni
the prototype of GBS, and other related immune polyneuropa- Mycoplasma pneumoniae
thies that cause acute generalized weakness but with different Typhoid
etiologies and pathophysiologies have been grouped together Shigella
and called GBS. These GBS types comprise most commonly Legionella pneumonia
the axonal subtypes of GBS, in which the primary pathology is Cyclospora
axonal degeneration and not segmental demyelination, includ- Systemic illnesses
ing acute motor axonal neuropathy (AMAN), a pure motor dis- Hodgkin’s lymphoma
Thyroid disease
order, and acute motor-sensory axonal neuropathy (AMSAN),
Addison’s disease
an acute mixed sensorimotor axonopathy (Table 28.2).
Leukemia
In addition to these three major subtypes of GBS, several
Paraproteinemia
GBS variants have been described. These variants deviate
Solid tumors (lung cancer)
significantly from the flaccid weakness and areflexia of typi- Sarcoidosis
cal GBS. Their link to GBS is supported by preceding infec- Systemic lupus erythematosus
tious episodes, diminished reflexes, elevated CSF protein Surgery
levels, and a presumed immune-mediated origin. Of these, Trauma
Miller Fisher syndrome is the most widely known, but others Vaccination
include facial diplegia with paresthesias, pure sensory or Pregnancy
ataxic forms, a pharyngeal-cervical-brachial regional form,
and an acute dysautonomia (see Table 28.2).
natural occurrence, was reported following the swine
influenza vaccination program in 1976 [11]. However, lack
Etiology of clarity in case ascertainment still generates controversy
regarding the validity of this association [12–14]. Nonetheless,
Although the topography, pathological features, pathophysi- the risk of developing GBS is one to two additional GBS
ology, prognostic features and, more recently, immunopatho- cases per one million vaccinated persons. The incidence of
genesis of GBS are well understood, the etiology of the GBS was higher among conventional influenza vaccinees
disease remains uncertain. There are no genetic factors that that were younger than 65 years, but the morbidity was
are known to predispose individuals to develop GBS, nor is higher among those older than 65 years [10]. Following the
there evidence that GBS is communicable. There have been recent pandemic swine flu in 2009, another specially designed
reports of clusters of cases without an obvious source, but H1N1-influenza vaccine was introduced. Though epidemio-
these have been thought to represent random variations [7]. logical studies from North America and Europe did not find
The association of GBS with vaccinations has been sus- an increase in incidence of typical GBS among contempo-
pected and debated for more than four decades. Reports of a rary H1N1-influenza vaccinees [15, 16], atypical GBS cases
definite association of GBS and conventional influenza, hep- and cases with GBS variants were recently reported [17].
atitis B, and Gardasil vaccines have been published [8–10]. An upper respiratory tract viral illness, diarrhea, or other
An “epidemic” of GBS, more accurately, an approximately infectious illness occurs 1–4 weeks before the onset of GBS
fivefold increase in the incidence of cases over the estimated in approximately two-thirds of patients (Table 28.3) [2, 18].
28 Guillain-Barré Syndrome and Related Disorders 575

In any individual case, the relationship between an antecedent formula in GBS [26]. GBS has also been reported following
illness and GBS may be less certain. Respiratory or gastroin- immune reconstitution from highly active retroviral immu-
testinal syndromes are the most common antecedent ill- notherapy [27].
nesses. In most patients, the infection resolves by the time Among other bacteria, Mycoplasma pneumoniae (M.
the neurological condition develops. pneumoniae) has been reported to precede GBS in approxi-
Campylobacter jejuni (C. jejuni) is the most frequently mately 5 % of cases and should be considered when weak-
identified bacterial infection preceding GBS. In addition to its ness develops after a prodromal illness characterized by
peculiarity of being a bacterial rather than a viral infection, it fever, headache, and severe dry cough [18]. Infection with
is implicated in up to 30 % of GBS cases studied prospec- M. pneumoniae is supported by the presence of cold aggluti-
tively with serological studies [19, 20]. Patients with C. jejuni nin antibodies in the serum and is confirmed by complement-
enteritis develop fever, watery diarrhea, and abdominal fixing antibody tests. Lyme disease is a bacterial illness
cramping with GBS typically developing days later. However, caused by a spirochete, Borrelia burgdorferi in the United
a substantial number of patients have only serological evi- States and Borrelia afzelii in Europe. It is transmitted by
dence of recent C. jejuni infection without enteritis [19]. C. infected hard ticks belonging to a few species of the genus
jejuni-related GBS has more severe axonal loss on electrodi- Ixodes. Lyme disease may cause a chronic axonal sensorim-
agnostic (EDX) studies, elevated anti-GM1 antibodies, and a otor polyneuropathy, a painful polyradiculitis (Bannwarth’s
more protracted recovery compared to cases without the syndrome), or acute facial diplegia [28, 29]. This may mimic
infection (see Sect. “Acute Motor Axonal Neuropathy” GBS, but the presence of a true postinfectious polyneuritis
below) [19, 21]. The immunologic implications of C. jejuni with Lyme is still somewhat uncertain. As with HIV, a lym-
as a triggering agent for GBS are of great interest because this phocytic pleocytosis in the spinal fluid may distinguish these
sequence of events supports postinfectious nerve inflammation patients from typical cases of GBS [28, 29]. Shigella, salmo-
as a pathogenetic theory. Certain strains of C. jejuni are the nella, typhoid, brucella, cyclospora, and yersinia enteroco-
cause of enteritis in a disproportionate number of GBS litica also have preceded GBS during epidemics or in single
patients [22]. The lipopolysaccharides of these organisms cases [30].
share ganglioside-like epitopes with peripheral nerves (such Several systemic illnesses also have been tenuously linked
as GM1, GQ1b, and GalNAc-GD1a) and are thought to to acute GBS, but most of these are implicated more often
induce a form of molecular mimicry in which the immune with CIDP. For example, a GBS-like syndrome has been
system, in its efforts to eradicate C. jejuni, elaborates antibod- described in patients with Hodgkin’s disease, lung cancer,
ies against neural antigens and secondarily produces GBS thyroid disease, systemic lupus erythematosus, paraproteine-
[21, 23]. mia, and sarcoidosis in single case reports or small series
The most commonly identified viral infection is cytomeg- [31, 32]. It is difficult to be certain that these are anything
alovirus (CMV), with serological evidence of preceding more than chance associations.
infection in 10–15 % of cases [18, 24]. In some instances, the Many GBS series have included a small proportion of
only indication that CMV is the preceding infectious agent cases that occurred after surgery, and only few cases genu-
may be an elevation in liver enzymes concomitant with the inely appear to have been triggered by an operation. It is now
onset of GBS symptoms. GBS triggered by CMV infection considered that some of these patients who develop weak-
tends to occur in younger individuals and to produce a more ness after being admitted to the intensive care unit have a
severe course with respiratory failure, prominent sensory “critical illness polyneuropathy” rather than GBS as a conse-
loss, more frequent cranial nerve involvement, and raised quence of multiorgan failure and sepsis or other factors asso-
antibodies directed against the ganglioside GM2 [18, 25]. ciated with a prolonged postoperative course in an intensive
Similarly, judging by serological studies, Epstein-Barr virus care unit (see Chap. 76). It is also unlikely that the axonal
infection precedes GBS in approximately 10 % of patients, loss and prognosis in GBS patients worsen after admission to
and the infectious clinical syndrome varies from mononucle- the intensive care unit due to concomitant critical illness
osis to pharyngitis or hepatitis [18]. The relationship between polyneuropathy [33]. Trauma has rarely been reported as a
GBS and other viruses reported to precede the condition, precipitant to GBS, and we have seen several such cases, but
such as respiratory syncytial virus, parainfluenza virus, echo- the association remains uncertain. In one study reported in
virus, coxsackie virus, measles, mumps, rubella, herpes 2006, 16 patients receiving tumor necrosis factor-alpha
zoster and simplex virus, influenza, and hepatitis A and B, is antagonist therapy developed GBS and were reported to the
less certain (see Table 28.3). GBS may occur soon after sero- US Food and Drug Administration [34]. Other medications,
conversion with human immunodeficiency virus (HIV) [26]. drugs of abuse, bone marrow transplantation, and spinal epi-
There are no clinical or EMG features that distinguish these dural anesthesia all have been reported to precede GBS, but
patients from non-HIV-related forms of GBS, except for a these connections also remain unproven. GBS may occur at
prominent lymphocytic pleocytosis in the spinal fluid of any time during pregnancy, but the risk is maximal during
patients with HIV, which may therefore complicate the CSF the first 2 weeks after delivery [35].
576 E.A. Piccione et al.

Pathogenesis of GBS [44]. Koski et al. demonstrated that elevated serum

levels of complement-fixing anti-myelin antibodies corre-
A number of immune mechanisms involving humoral and lated with disease activity in patients with GBS [45, 46].
cellular immunity, complement deposition, proinflammatory Recent autopsy studies revealed that local complement acti-
cytokines, and other inflammatory mediators are theorized to vation occurs at the site of nerve lesion, such as the axo-
be involved in the pathogenesis of GBS [36]. Many of these lemma in patients with AMAN and the Schwann cell mem-
purported mechanisms have been gleaned from studies in an brane in patients with AIDP [47, 48]. There is now evidence,
experimental model of the disease—experimental autoim- using high-resolution immunocytochemistry, of early com-
mune neuritis (EAN) that represents a fair version of the plement activation and deposition of activated complement
human disease. The extent to which each of these immune components along the outer surface of the Schwann cell. The
processes is related to various clinical and electrophysiologi- presence of terminal complement complex is associated with
cal patterns, and the implications for treatment and progno- vesiculation of the outermost myelin lamellae. This occurs
sis, is of great interest but has not been fully studied. In EAN, before and within 1 week of invasion of macrophages [48].
rabbits, guinea pigs, or rats are immunized with autologous In patients with AMAN associated with axonal loss, the
peripheral nerve tissue and Freund’s adjuvant (a nonspecific complement activation product binds to the axolemma of
stimulator of immune reactions). After a latency of several motor fibers and, in severe cases, immunoglobulin and acti-
days, they develop a rapidly progressive paralytic illness vated complement within the periaxonal space of myelinated
with the pathologic features of endoneurial inflammation internodes [47].
and demyelination, identical to the clinical and pathological Numerous studies have demonstrated the presence of
manifestations of GBS [37]. This inflammatory response is anti-neural antibodies directed against acidic glycoconju-
mediated by T cells that are directed against epitopes on gates in the serum of patients with GBS. These peripheral
peripheral nerve myelin including PO, P2, and PMP 22, and nerve antigens are usually gangliosides (GM1, GD1a, GQ1b,
by implication, this immune attack leads to macrophage and GT1a) which differ with regard to the position and num-
invasion and demyelination [38]. ber of their sialic acid. There is solid indication that anti-
In classical pathological studies of GBS, demyelination ganglioside antibodies play a pathogenic role in the
was most prominent adjacent to regions of intense perivenu- pathophysiology of GBS [49]. In clinical practice, these anti-
lar inflammation [39, 40]. Pathological material from patients bodies are found in only a minority of patients since autoan-
with GBS shows a similar accumulation of lymphocytes and tigens have not been well identified in AIDP. The anatomic
macrophages in a perivascular distribution scattered through- distribution of the gangliosides within the peripheral nervous
out the peripheral nervous system with a predilection for spi- system may explain some of the observed clinical variants of
nal roots [39–41]. Macrophages and T cells express major GBS [36, 49]. For example, GQ1b is strongly expressed in
histocompatibility (MHC) class II antigens which are upreg- the oculomotor, trochlear and abducens nerves, as well as the
ulated on Schwann cells in the region of inflammatory lesions muscle spindles in the limbs, which explain the distinct
in patients with GBS. One hypothetical sequence that has Miller Fisher syndrome (ophthalmoplegia, ataxia, and
been offered is that activated T cells, stimulated by a preced- areflexia), frequently associated with anti-GQ1b antibody
ing infection and by an interaction with antigen presenting [50–52]. There is also strong evidence currently that the
cells that express MHC class II antigens, disrupt the blood axonal subtypes of GBS, particularly AMAN and less com-
nerve barrier, attack endoneurial antigens, and release monly AMSAN, are associated with antibodies directed
inflammatory cytokines such as interleukin-2 and tumor against GM1 and GD1a at the axolemma. This eventually
necrosis factor (TNF) [36]. In keeping with this hypothesis, attracts macrophages invading the nodes of Ranvier and
several investigators have demonstrated elevated levels of inserting between the axon and the axolemma, resulting in
TNF and soluble TNF receptor in the serum of patients with axonal degeneration. In AMAN, the myelin sheath also
acute GBS [42, 43]. These cytokines attract macrophages remains intact, and there is no lymphocytic inflammation
that are capable of producing nerve demyelination and dam- [53]. In AMAN, only the axons of the ventral roots are
age Schwann cells and axons [36, 42, 43]. involved, while in AMSAN, both the dorsal and ventral roots
There is also evidence that humoral factors are central to are affected [38, 41].
the development of GBS. Passive transfer studies have shown Increasing evidence supports that molecular mimicry
that sera from GBS patients injected into the nerves of ani- plays an important role in the pathogenesis of GBS. It is
mals induces local demyelination. Furthermore, the observed likely that genetic polymorphism in various strains of C.
clinical recovery following removal or neutralization of jejuni determines the specificity of the antiganglioside anti-
autoantibodies (or other pathogenic humoral factors) by bodies and the associated variant of GBS. Lipooligosaccharide,
plasmapheresis or intravenous immune globulin (IVIG) sup- a major component of the outer membrane of C. jejuni, has
ports a role for B-cell-mediated processes in the pathogenesis ganglioside-like products; sensitization with GM1-like
28 Guillain-Barré Syndrome and Related Disorders 577

lipooligosaccharide by injecting it, rabbits induced a neu- Table 28.4 Frequency of clinical features in Guillain-Barré syndrome
ropathy resembling AMAN [54]. C. jejuni bacterial isolates Initially In fully developed Illness
from patients with AMAN have GM1-like and GD1a-like Paresthesias 70 85
lipopolysaccharides, whereas bacterial isolates from patients Weakness 98
with the Miller Fisher syndrome usually express GQ1b-like Legs > arms 54
lipopolysaccharides [55, 56]. It is now evident that C. jejuni Arms > legs 14
is composed of several classes that have diverse lipooligo- Approximately equal 32
Ophthalmoparesis 5 15
saccharide biosynthesis genes. C. jejuni is now grouped into
Facial weakness 35 50
several classes based on the organization of these genes. A
Bulbar weakness 25 50
specific class carrying a sialyltransferase gene (cst-II) is
Respiratory failure 10 30
associated with the development of GBS. Patients infected Ataxia 10 15
with a specific strain (Thr51), which expressed both GM1- Sphincter dysfunction 15 5
like and GD1a-like lipooligosaccharides, had anti-GM1 or Areflexia 75 95
anti-GD1a IgG antibodies and present with typical GBS Pain 25 30
manifestations including limb weakness. In contrast, patients Sensory loss 40 85
infected with another strain (Asn51), which expresses GT1a- Reprinted with permission from Ropper [59]
like or GD1c-like lipooligosaccharides, have anti-GQ1b IgG
antibodies and present with the Miller Fisher syndrome
including ophthalmoplegia and ataxia [55–58]. On the basis that is similar in the arms and legs. Fasciculations or myo-
of the above findings, one may conclude that C. jejuni-asso- kymia are observed in a small number of patients.
ciated/GM1-related GBS represents at least true instance of The second hallmark sign of GBS is reduced or absent
a molecular-mimicry-related disease. deep tendon reflexes, presumably reflecting desynchroniza-
tion or dispersion of impulses carried by myelinated fibers in
the afferent arm of the reflex arc. Approximately 70 % of
Clinical Features patients have absent deep tendon reflexes at the time they are
first examined. Reflexes occasionally remain elicitable until
GBS in its typical form is a predominantly motor neuropa- weakness or large fiber sensory loss advances. Reflexes are
thy, although acral paresthesias are almost always present at almost always unobtainable in limbs that are too weak to
the onset of the illness (Table 28.4). Tingling, prickling, or resist gravity. Yuki et al. found that the myotatic reflexes
pins and needles sensations are usually followed within were normal or exaggerated during the entire clinical course
hours or days by symmetrical leg weakness and trouble in approximately 10 % of GBS patients, more commonly in
walking. The presence of acral paresthesias increases the patients with AMAN than AIDP [60]. However, the diagno-
probability of the correct diagnosis of GBS [2]. Difficulty sis of GBS must remain questionable in this group, and upper
climbing stairs or arising from a chair or commode is typical. motor neuron causes of weakness should be excluded.
Weakness of the upper limbs, ocular, oropharyngeal, and More than half of GBS patients experience paresthesias
facial muscles develops with variable frequency and of the distal extremities as the initial symptom. Most patients
severity. complain of “pins and needles,” “prickling,” or “tingling”
The weakness is often bilateral but some degree of asym- feelings, likened to an “asleep feeling” in an arm or leg fol-
metry is common. Rarely, the weakness begins in one limb lowing compression of the limb. In contrast to most length-
hours or a day before involving the contralateral limb. dependent axonal polyneuropathies, patients with GBS often
Proximal weakness is more frequent than distal and often develop paresthesias in the fingertips soon after the feet are
more severe. In contrast to diseases that affect the muscle or affected and sometimes beforehand. The sensory symptoms
neuromuscular junction, weakness rarely remains restricted are symmetric and often precede weakness by a few days,
to the shoulder or hip girdle muscles; some degree of hand or ascending to the ankles and wrists as the illness progresses.
distal leg weakness develops after the proximal muscles. The Paresthesias of the trunk or face are infrequent. Patients may
weakness often moves to the upper limbs resulting in an also describe an acral numb, heavy, or dead sensation as the
ascending paralysis. Weakness that remains limited to the disease evolves. Some experience sensory loss over the
legs or, alternatively, weakness that begins in the hands or trunk, and a well-demarcated sensory level simulating spinal
shoulder girdle and involves the legs may occur as the condi- cord disease has been described, but only to the extent of a
tion advances. A pattern of descending paralysis occurs in noticeable change in sensation, not analgesia below the level.
10–15 % of cases, with symptoms beginning in the cranial The detection of a genuine thoracic sensory level should
nerves or arms and spreading to the legs. Approximately prompt further evaluation with an MRI of the spinal cord to
one-third of fully developed cases have a degree of weakness exclude a myelopathy including transverse myelitis. Reduced
578 E.A. Piccione et al.

vibration sense and proprioception in the distal limbs are the and mild hypoxia. These changes further aggravate ventila-
most common findings. A substantial number have sensory tory failure by causing tachypnea and an increased work of
ataxia that is soon obscured by weakness. Pinprick sensation breathing. As the respiratory rate increases, levels of carbon
may also be impaired in distal parts in severely affected dioxide actually may be reduced in the early stages of respi-
patients. ratory compromise. However, as the diaphragm, intercostal,
Pain is a common but underappreciated symptom in GBS. and accessory muscles become further exhausted, hypercap-
Pain may precede the onset of weakness by 2 weeks in 1/3 of nea ensues and patients may rapidly deteriorate with hyper-
patients [61], and about 2/3 of patients have modest discom- carbia and respiratory arrest. If diaphragmatic and respiratory
fort early in the illness [62]. Pain, when not severe, may be muscle weakness have not occurred 2 weeks into the course
overlooked by medical staff who are preoccupied with more of the illness, assisted ventilation should not be necessary
pressing medical complications, and intubated patients often unless other pulmonary or medical complications ensue. The
are unable to convey their discomfort. The discomfort in main predictors of mechanical ventilation include shorter
GBS has been described as (1) aching, usually confined to days between onset of weakness and admission, higher
muscles of the back, hips, or upper legs (the most common Medical Research Council (MRC) sum score, and presence
type); (2) shooting or stabbing, radicular pain radiating from of facial and/or bulbar weakness (see Sect. “Prognosis”)
the back to one or both legs; or (3) chronic and unrelenting, [65]. Patients with GBS who require ventilator support have
burning, dysesthetic feelings in the distal limbs [61–63]. a less favorable prognosis for neurologic recovery, longer
Rarely, back and radicular pain can precede weakness and hospitalization, and higher mortality.
paresthesias and be attributed to sciatica or a spinal condition Dysautonomia is a less common but well-recognized fea-
[63]. At 1-year follow-up, pain is reported in 38 % of patients, ture in patients with fully developed GBS, occurring up to
and the pain intensity was highest in patients with typical 65 % of cases [68, 69]. This number is certainly overesti-
GBS and in those with sensory disturbances and with higher mated if one considers only changes of clinical significance.
level of weakness and disability [61]. Autonomic nervous system complications tend to occur more
Approximately one-half of GBS patients will have cra- frequently in those with severe paralysis and ventilatory
nial nerve involvement at some time in the course. The facial difficulties, but rarely may develop in otherwise mild cases.
nerve is most commonly affected, and facial weakness typi- The most common cardiac manifestations include sinus
cally occurs when there is substantial limb weakness. tachycardia, sinus bradycardia, sinus arrest and other
Conversely, lack of facial weakness in a patient with severe supraventricular arrhythmias, paroxysmal hypertension,
generalized paralysis should at least raise concerns about the hypotension (especially postural hypotension), and so-called
accuracy of the diagnosis. As with limb weakness, facial vagal spells that consist of bronchorrhea, bradycardia, and
paralysis is often bilateral, but occasionally asymmetrical, hypotension. Infection, hypoxia, pulmonary embolus, and
and rarely unilateral. Weakness of the ocular muscles arises other medical complications should be excluded before attrib-
in 10–20 % of patients, the abducens nerve being most com- uting cardiovascular disturbances to dysautonomia. Because
monly affected. Impaired abduction is usually bilateral and of the potential for complete heart block, sinus arrest or other
occasionally asymmetrical. Oropharyngeal weakness occurs life-threatening cardiac arrhythmias (e.g., ventricular tachy-
in up to one-half of patients during the course of the illness cardia), and the risk of rapidly progressive respiratory failure,
and presents great problems in terms of aspiration. In severely most patients with GBS require monitoring in an intensive
affected patients, there may be paralysis of all the cranial care setting early in the illness (see Sect. Supportive Care in
muscles, ventilatory failure, and flaccid paralysis of all the under the Sect. Treatment and Management). Other features
limbs, simulating the “locked-in” state [64]. of autonomic instability include ileus, urinary retention (sur-
Weakness of the diaphragm that leads to respiratory fail- prisingly common—seen in one-quarter of patients and sug-
ure and a requirement for ventilator support occurs in approx- gesting a myelopathy), and inappropriate antidiuretic hormone
imately 20–30 % of patients with GBS [65–67]. Most such secretion leading to hyponatremia [70]. Many patients have
patients are quadriparetic, although patients with a bibrachial minor aspects of dysautonomia that are clinically insignificant,
pattern of weakness may also have pronounced oropharyn- such as altered sweating, mild orthostatic hypotension, and
geal and respiratory muscle involvement (see Sect. “Guillain- acral cyanosis from vasomotor instability.
Barré Syndrome Variants”). Weakness of the neck muscles, GBS can have sometimes unusual features such hearing
tongue, and palate tends to parallel involvement loss, meningeal signs, vocal cord paralysis, papilledema, and
of the diaphragm and respiratory muscles. Diaphragmatic mental status changes [71]. Recently, cases of GBS has been
weakness, which causes reduced vital capacity, inspiratory associated with posterior reversible encephalopathy syn-
force, and tidal volume, invariably causes atelectasis. drome (PRES) [72]. One explanation for the PRES is that the
Coughing and clearing of oral secretions are then impaired, cytokines, produced in the context of GBS, may increase the
generating progressive atelectasis, arteriovenous shunting, permeability of the blood–brain barrier.
28 Guillain-Barré Syndrome and Related Disorders 579

Guillain-Barré Syndrome Subtypes conduction blocks, normal sensory potentials, and early
active denervation, thus implicating a process similar or
For many years, the term AIDP was interchangeably used identical to AMSAN, with the exception of the normal sen-
with GBS. It is now well recognized, particularly during the sory potentials (see below) [79–81].
last two decades, that axonal forms of GBS exist and these Autopsy findings have confirmed widespread axonal
are distinguished from AIDP using electrophysiological and degeneration with little demyelination or inflammation [48,
pathological characteristics. These disorders, AMAN and 81]. Pathologic studies using electron microscopy have dem-
AMSAN, remain under the same umbrella term of GBS onstrated the presence of macrophages in the periaxonal
because they share many of the clinical findings, including space of myelinated internodes [48, 53, 87]. The pathogene-
flaccid weakness and areflexia, preceding infectious episode, sis of AMAN has not been fully elucidated, but there is con-
and a presumed immune-mediated origin (see Table 28.2). vincing evidence for an antibody- and complement-mediated
These disorders are also often preceded by infections, but process directed primarily at motor axons. There is evidence
may be occasionally associated with connective tissue disor- to suggest that IgG anti-GM1 or anti-GD1a antibodies bind
ders [73, 74]. Also, these disorders may be difficult to distin- to the axolemma at the node of Ranvier leading to membrane-
guish on early electrodiagnostic studies since the nerve attack complex formation. This results in the loss of voltage-
conduction changes may overlap and sequential studies are gated sodium channels and leads to conduction failure. These
often necessary. rapidly reversible immune-mediated changes at the nodes of
Ranvier may explain the puzzling speedy recovery that
Acute Inflammatory Demyelinating occurs in some patients with AMAN, a rate that is compara-
Polyradiculoneuropathy (AIDP) ble to patients with AIDP. Another explanation for the rapid
AIDP is the prototype of GBS and characterized by periph- recovery is selective degeneration and subsequent quick
eral nerve and spinal root demyelination. This disorder regeneration of intramuscular motor nerve terminals in
accounts for up to 90 % of GBS cases in North America and AMAN [86, 88, 89].
Europe [75] but only 22–46 % of cases in China, Japan,
India, Southeast Asia, and Mexico [76, 77]. This disorder is Acute Motor-Sensory Axonal Neuropathy (AMSAN)
characterized by vesicular degeneration of myelin triggered In 1986, Feasby and coworkers described an axonal form of
by membrane-attack complex formation on the outer surface GBS, challenging the existent notion of GBS being a primar-
of Schwann cells. AIDP has not been strongly associated ily demyelinating disease. These patients developed rapidly
with antiganglioside antibodies [78]. progressive paralysis, areflexia, and distal sensory loss [90,
91]. All of their patients required assisted ventilation and
Acute Motor Axonal Neuropathy (AMAN) recovery was poor. The spinal fluid protein level was
McKhann, Griffin, and colleagues described an acute para- increased, but in contrast to the demyelinating features of
lytic syndrome in patients from regions of northern China typical GBS, EDX evaluation showed numerous inexcitable
and coined the term acute motor axonal neuropathy (AMAN) nerves, widespread active denervation, and no evidence of
[79–81]. It is now clear that this disorder is as common as demyelination. An autopsy in one case showed axonal degen-
AIDP in Mexico, China, Japan, India, and Southeast Asia, eration without inflammation or primary demyelination in
accounting for 30–65 % of cases [76, 77]. In contrast, AMAN the spinal roots and peripheral nerves. Since then, several
is rare in North America and Europe, probably accounting studies have suggested that this syndrome, now termed acute
for less than 10 % of cases [75]. motor-sensory axonal neuropathy (AMSAN), represents a
The disorder primarily afflicts children and young adults variant of GBS that is clinically indistinguishable from typi-
[79, 82] and causes symmetrical limb weakness, areflexia, cal, albeit very acute, cases but in which axons are the targets
facial diplegia, and oropharyngeal and respiratory muscle of the immune reaction. Virtually all patients become quad-
weakness that evolves over several weeks. The extraocular riplegic within days and require ventilator support and most
muscles are spared. There are no sensory features although have substantial residual weakness after recovery from the
mild changes in sensory nerves may occur [83]. The condi- acute illness; some remain ventilator dependent for pro-
tion occurs as an annual epidemic during summer months. longed periods. Nerve conduction studies indicate an acute
Most cases are preceded by a gastrointestinal illness with and widespread axonal sensory and motor neuropathy with-
abdominal pain, cramps, and diarrhea and elevated antibody out demyelinating features.
titers to Campylobacter jejuni, anti-GM1, and anti-GD1a It has also been argued that complete, distal conduction
[84–86]. The spinal fluid protein concentration is usually block and reversible conduction failure can simulate the
slightly elevated after several days of the illness, but EDX finding of nerve inexcitability that is at the core of the diag-
studies show reduced or absent compound muscle action nosis [92]. Subsequent pathological material from a few
potential amplitudes with normal conduction velocities, no cases has shown axonal degeneration in the motor nerves
580 E.A. Piccione et al.

with macrophages insinuated in the periaxonal space of is the most sensitive EDX test. However, absent H-reflexes are
internodes; some patients also had axonal loss in the spinal not specific for GBS since it a common finding in the elderly
roots [41]. and occurs in the majority of large fiber sensory and senso-
Recent evidence suggests that AMAN and AMSAN share rimotor peripheral polyneuropathy such as diabetic and criti-
a common immunological profile and represent a continuum cal illness polyneuropathies, as well as S1 radiculopathies,
within the spectrum of axonal GBS [41]. Anti-GM1, anti- cauda equina, and conus medullaris lesions.
GM1b, and anti-GD1a, immunological markers for AMAN,
are seen in high percentage of patients with AMSAN [93]. Abnormal F-Waves
Also, sensory fiber involvement which distinguishes AMSAN Multifocal acquired nerve demyelination, the hallmark of
from AMAN has been shown to be often involved subclini- GBS [6], preferentially affects proximal and distal portions
cally in AMAN patients [83]. of the peripheral nerves [101]. Therefore, a common
finding in early GBS is prolonged F-waves [94–96].
Prolonged or absent F-responses have been reported in as
Evaluation and Diagnosis many as 40–80 % of GBS patients early in the illness [100,
102]. It may be the sole electrodiagnostic abnormality in
Electrodiagnostic Studies about one-fourth of patients [101, 102]. The yield of
F-wave studies improves by assessment of additional mul-
Electrodiagnostic (EDX) studies are very important in the tiple F-wave parameters, including chronodispersion,
diagnosis of GBS. Abnormalities on nerve conduction stud- mean latency, and mean amplitude [101]. However, these
ies (NCS) are seen in up to 95 % of cases, and these findings parameters are difficult to quantitate and are subject to
are diagnostic in large number of GBS patients at some time variability.
during the course of the illness [94–96]. Unfortunately, NCS
may be normal or show only modest nondiagnostic changes Multiple and Complex A-Waves
early in the course of GBS, at a time when treatment deci- A-waves are reproducible intermediate-to-late responses
sions have to be made. Repeat studies are often necessary, that are distinguished from F-waves and H-reflexes and
particularly when initial NCS findings are not specific [94]. usually seen during routine F-wave studies. A-waves may
The nature of the abnormalities detected by NCS depends be recorded in normal individuals of the foot muscles while
upon the timing of the study in relation to disease onset and stimulating the tibial nerve. A-waves are commonly seen in
the number of nerves studied. Extensive testing of multiple multiple nerves and often with complex morphology in
nerves and multiple nerve segments in multiple limbs includ- about 2/3 of patients with GBS [103, 104]. Their precise
ing evaluation of F-waves, H-reflexes, and blink reflexes is mechanism is not known, but they may be due to ephaptic
essential. The aim of NCS is to show evidence of multifocal transmission between axons or proximal re-excitation of
acquired nerve demyelination, the hallmarks of AIDP, which the axon. Although prevalent in GBS, A-waves are not
represents the majority of patients with GBS in the Western specific for GBS since they may be seen in other acquired
World [75]. and inherited demyelinating polyneuropathies (such as
chronic inflammatory demyelinating polyneuropathy and
Abnormal Electrodiagnostic Parameters in GBS Charcot-Marie-Tooth disease type I) and, less often, in
The EDX studies in GBS include a variety of NCS parame- axonal polyneuropathies, radiculopathies and motor neuron
ters which may become abnormal during the course of ill- disease [103].
ness. These include motor distal latencies, motor conduction
velocities, CMAP amplitude and waveform configuration, Motor Conduction Blocks
sensory studies, late responses, and needle EMG. Although This is defined as a reduction (usually >20–50%) in the
these EDX abnormalities are common in GBS, they vary in amplitude and area of the compound motor action potential
specificity which renders some of them less useful than oth- (CMAP) following proximal nerve stimulation (Fig. 28.1).
ers. The following are the most common abnormalities seen To be more specific and to avoid confusing GBS with poly-
in GBS, with varying degree of specificity: neuropathies associated with compressive mononeuropa-
thies, the conduction blocks in GBS should be located at
Abnormal H-Reflex non-entrapment sites (Fig. 28.2). This is a highly specific
The tibial H-reflex is a sensitive test for detecting abnormali- finding but is found in only about one-third of patients with
ties of the S1 nerve root and early polyneuropathy and corre- GBS, dependent on the number of nerves and nerve segments
lates fairly well with the Achilles reflex [97]. Absent H-reflexes studied [95, 98, 100]. Conduction block is often a sign of
correlate well with the areflexia in the lower extremities of segmental demyelination, but transient conduction and block
GBS patients. The H-reflexes are absent bilaterally in almost may be seen as the early manifestations of axonal loss such
all patients with GBS, including in 95–100 % of patients dur- during the early stages of AMAN [105, 106]. Sequential
ing the first 1–2 weeks of illness [98–100]. Hence, the H-reflex studies are necessarily before a final diagnosis of axonal loss
28 Guillain-Barré Syndrome and Related Disorders 581

2 mV/D 3 ms/D

dLAT/CV AMP AREA

4.2 2.7 8.6

18.9 m/s 0.5 2.1

Fig. 28.1 Median motor nerve conduction study in a 35 year old stimulation at the wrist (upper tracing) is compared to proximal
patient with GBS examined at week 2 of illness. Note the forearm stimulation at the elbow (lower tracing). There is also marked slowing
conduction block as evidenced by the significant drop in CMAP of forearm conduction velocity (18.9 m/s). dLAT/CV distal latency/
amplitude (80 %) and area (76 %) when CMAP obtained with distal conduction velocity, AMP amplitude

2 mV/D 5 ms/D

dLAT/CV AMP AREA

4.8 4.4 15.4

20.9 m/s 0.7 1.9

30.5 m/s 0.1 0.3

Fig. 28.2 Peroneal motor nerve conduction study in a 55 year old is compared to proximal stimulation below fibular neck (middle tracing)
patient with GBS examined at week 4 of illness. Note the significant and popliteal fossa (lower tracing). The conduction block is distal to the
drop in CMAP amplitude (84 %) and area (88 %), with CMAP dispersion, fibular neck, not at a common entrapment site (i.e., fibular tunnel). dLAT/
when CMAP obtained with distal stimulation at the ankle (upper tracing) CV distal latency/conduction velocity, AMP amplitude

is made. Also, low distal CMAPs may be due to distal demy- remyelination [95]. Additionally, controversies remain
elination with distal conduction block and often mimic regarding the exact cutoff of conduction velocity that distin-
axonal loss. Rapid recovery of low distal CMAPs and SNAPs guishes primary demyelination from axonal loss, particularly
on sequential studies is a necessary confirmatory sign of dis- in the presence of low CMAP amplitude. These values have
tal demyelination [106]. varied from 60 to 80 % of the lower limits of the normal
conduction velocity values [94, 95, 107].
Nerve Conduction Velocities Slowing
Significant slowing of nerve conduction velocities was first Distal Latency Slowing
reported by Lambert and Mulder who reported in 60 % of Since multifocal acquired nerve demyelination in GBS
their patients with GBS. During the early stage of disease, preferentially affects proximal and distal portions of the
however, 80–90 % of patients with AIDP have normal con- peripheral nerves, common findings in early GBS are
duction velocities [95]. It is now clear that prominent slow- prolonged distal motor latencies [94, 95]. Although this
ing of nerve conduction velocities is uncommon and is finding is common, it lacks specificity except when the
detected in only approximately 25 % of cases [98, 100]. latencies are significantly delayed and are within the demy-
Slowing is particularly uncommon during the first 2 weeks elinating ranges. Similar to velocities, these ranges have
of illness in AIDP, and conduction velocities become para- also been controversial since demyelinating ranges have
doxically slower between 3 and 6 weeks from onset and dur- varied from 120 to 150 % of the upper limit of normal
ing the recovery phase, presumably due to nerve fiber values [107–110].
582 E.A. Piccione et al.

Compound Muscle Action Potentials (CMAPs) substitute for sural-sparing pattern. Patients with AIDP are
Dispersion 12 times more likely to have an elevated sensory ratio (>1)
The CMAP duration may be prolonged in GBS, and this is compared to patients with axonal polyneuropathies such as
attributed to varying degrees of conduction slowing in demy- diabetic or critical illness polyneuropathies [115]. It is not
elinated motor nerve fibers. Dispersion of the CMAP has known whether another lower limb SNAP, such as the
only been considered as a criterion of demyelination in one superficial peroneal, could substitute for the sural.
study [108, 109]. Adding this fairly specific finding to other
EDX parameters improved the sensitivity of EDX studies Needle Electromyography (EMG)
without worsening its specificity [111]. Distal CMAP Needle EMG is the least helpful EDX tool in the evaluation of
durations of median, ulnar, peroneal, or tibial nerves measur- patients with GBS, mostly since the EDX studies are often
ing more than 8.5 ms are strong evidence for the presence of done early in the disease before signs of axonal degeneration
demyelination [111, 112]. are apparent on needle EMG. The initial finding in patients
with GBS is reduced recruitment with the degree of abnor-
Abnormal Sensory Nerve Action Potentials (SNAPs) mality proportional to the degree of muscle weakness. Early
Earlier EDX criteria of GBS overlooked sensory nerve conduc- on, the combination of normal or virtually normal motor unit
tion studies by emphasizing abnormalities of motor NCS, such action potentials (MUAPs), reduced MUAP recruitment, and
as conduction block, CMAP dispersion, abnormal F-waves, absent fibrillation potentials detected by needle EMG is char-
and slowing of latencies and velocities. It is now clear that acteristic. However, similar needle EMG findings are also
SNAPs abnormalities are common and sometimes specific for seen in other acute axonal nerve lesions. The detection of
AIDP. SNAP are abnormal in about 75 % of patients some- abnormal spontaneous activity (fibrillation potentials) indi-
times during the illness [94, 95, 100, 102]. The most common cates axonal damage and occurs in 20–60 % of GBS patients
findings are reduced SNAPs amplitudes. This may reflects in the first 4 weeks of the illness [95, 107]. This is seen in the
axon loss but is more likely caused by conduction block and demyelinating and axonal subtypes of GBS and signifies a
phase cancellation. Slowing of sensory nerve conduction variable element of axonal loss in all patients. Abnormal
velocities is detected less frequently because the SNAP poten- spontaneous activity is found more often during follow-up
tial usually drops out before severe slowing is found. studies, 2–4 months after onset, and may be observed in prox-
Sensory NCS is now recognized to be important in pro- imal and distal muscles, consistent with multifocal nerve
viding EDX evidence that might distinguish primary demy- degeneration [95]. MUAP morphology changes start to occur
elinating from axonal polyneuropathy. A sural-sparing after the fourth week of illness with an increased percentage
pattern, also known as a “normal sural-abnormal median” of polyphasic MUAPs as the early change. Myokymia may
pattern, is now recognized to be a common and specific be found in limb or facial muscles in some GBS patients, usu-
finding in GBS and in particular AIDP [94, 100, 113, 114]. ally early in the course of the disease [94].
In contrast to the majority of length-dependent axonal poly-
neuropathies, the median and ulnar SNAPs are frequently Electrodiagnostic Criteria in GBS
reduced or absent when the sural nerve is normal (“sural Various sets of EDX criteria for the detection of demyelina-
sparing”), presumably as a consequence of random, multifo- tion have been developed. These were mostly made by con-
cal demyelination. This pattern is the most specific sensory sensus or as part of the methods utilized in GBS studies [94,
abnormality in AIDP and is present in about 50 % of patients 95, 107, 109, 110]. However, most of these criteria were not
during the first 2 weeks of illness [98, 100]. subjected to vigorous scrutiny or applied to other neuropa-
There are several limitations of the sural-sparing pattern thies, and their specificities in GBS diagnosis were not well
which affects its sensitivity and specificity in the diagnosis of tested. For example, classic published diagnostic criteria of
GBS. First, the sural SNAP may be either low in amplitude AIDP in GBS are fulfilled in 20–70 % of the cases based on
or absent in elderly patients and in those with underlying the specific criteria utilized [99, 116]. This variation depends
diabetic polyneuropathy [98]. Second, technical consider- on how strict these criteria are in excluding patients with
ations in hospitalized or critically ill patients or those on equivocal EDX findings.
mechanical ventilation render it difficult to study the sural Although it is intuitive to conclude that EDX studies are
SNAP. Third, the median sensory study may be abnormal in sensitive in confirming demyelination, EDX studies often
patients with preexisting carpal tunnel syndrome. Hence, reveal abnormalities that are not specific of primary demyeli-
sural sparing is better defined by preservation of sural SNAP nating polyneuropathy during the early phases of the disease.
in the presence of normal or near normal median and ulnar Common abnormalities seen during the first few weeks of ill-
SNAPs in the upper extremity [98, 100]. ness include absent or delayed H-reflexes, F-responses or
Comparing several SNAP amplitudes in the upper and blink reflexes, “sural sensory sparing,” distal CMAP temporal
lower extremities is a useful exercise, particularly in elderly dispersion, or frequent A-waves [95, 98–100]. During the
where the sural may be unobtainable. Among them, a sensory first 4 days of weakness GBS, about 1/2 of the patients have
ratio (sural + radial SNAPs/median + ulnar SNAPs) is a good normal NCSs (except for absent H-reflex in the majority of
28 Guillain-Barré Syndrome and Related Disorders 583

Table 28.5 Diagnostic power of nerve conduction studies findings in the first 2 weeks of patients with AIDP
Abnormalities Sensitivity (%) Specificity (%)
1. Nondiagnostic Nonspecific abnormalities that are not specific for – 19
GBS, including absent H-reflexes, borderline or low
CMAPs and/or SNAPs, minimal slowing of latencies
or velocities
2. Suggestive Upper extremity sensory sparing pattern 26 86
or
Absent or prolonged minimal F-wave latencies in at
least 2 motor nerves with absent H-responses
3. Highly suggestive Upper extremity sensory sparing pattern 29 96
and
Absent or prolonged minimal F-wave latencies in at
least 2 motor nerves with absent H-responses
4. Definite Signs of multifocal demyelination including: 35 100
1. Marked slowing of motor conduction velocity,
distal latency and temporal dispersion
2. Conduction blocks in at least 2 motor nerves
3. Absent or prolonged minimal F-wave latencies in at
least 2 motor nerves with absent H-responses
Highly suggestive or 3 and/or 4 64 96–100
definite findings
SNAP sensory nerve action potential, CMAP compound muscle action potential

them), while only about 10 % of them have normal studies by tudes typical of distal demyelination as seen in AIDP [92]. A
the first week of illness [98]. Another 5–10 % have only useful diagnostic clue is the time course of EDX abnormali-
nonspecific nerve conduction abnormalities, such as mild ties. The nadir of conduction slowing in AIDP is 3–6 weeks
slowing, absent and/or prolonged H-reflexes or F-waves (due after onset of symptoms, and this corresponds with the begin-
to spinal root demyelination), or low-amplitude CMAPs (due ning of the clinical improvement [95]. In contrast, when con-
to intramuscular motor nerve terminals involvement). duction slowing or block is present in AMAN, it is evident
We recommend using EDX criteria that include these dif- early during the first 3 weeks of illness and rapidly resolves in
ferent variables and have increasing levels of certainty in parallel with clinical improvement [106, 117].
confirming the diagnosis of demyelination in AIDP [100]
(Table 28.5). These criteria are designed to grade the level of Prognosis of GBS Using Electrodiagnostic Studies
confidence of the EDX studies, ranging from normal study to It has been long known that this presence of axonal damage
definite findings of acquired multifocal demyelination. Using in GBS is generally associated with worse outcome. In con-
these criteria, about 2/3 of patients with GBS meet the highly trast, there is no association between slowing of nerve con-
suggestive or definite criteria for AIDP during the first two duction velocities or F-wave latencies and clinical recovery.
weeks of illness with a very high specificity of 96–100 %. Early studies indicated a relationship between the detection
The remainder likely includes patients with the axonal sub- of fibrillation potentials and poor outcome [118], but others
types of GBS, AMAN, and AMSAN, who do not have evi- have failed to confirm this finding as fibrillation potentials
dence of demyelination. may occur when minimal amount of axonal loss has occurred
[75, 107]. Also, fibrillation potentials may take several weeks
Electrodiagnostic Studies in GBS Subtypes to appear which renders needle EMG findings less useful.
The EDX studies in GBS and its subtype may be confusing at Reduced CMAP amplitude is the most important predic-
the early stage of the disease when it is often difficult to deter- tor of outcome in GBS. Reduced mean CMAP amplitude
mine the subtype classification of the disease (axonal vs. (<20 % of the lower limit of normal) or absent CMAPs are
demyelinating) [105]. AIDP, AMAN, and AMSAN may have strongly associated with a poor prognosis [66, 75, 119].
similar findings during the first weeks of illness. As outlined Hadden and colleagues demonstrated that 42 % of patients
above, sensory conduction abnormalities are seen in patients with an axonal loss pattern, on follow-up studies, were non-
with AMAN, making the distinction with AMSAN sometimes ambulatory after 48 weeks [75]. On individual basis, one
difficult [83]. Also, transient conduction slowing and block should be careful in making definite prognostic implications
may be encountered during the early stages of AMAN, lead- based on EDX studies only during the first 2–3 weeks of ill-
ing to incorrect diagnosis of AIDP [106, 117]. Similarly, some ness for several reasons: (1) Patients with axonal GBS studied
patients initially classified as “axonal” by nerve conduction early may show normal CMAP amplitude before the onset
studies have distal conduction block, and follow-up studies and completion of Wallerian degeneration [120]; (2) EDX
demonstrate rapid recovery of motor and/or sensory ampli- evidence of conduction block when the site of stimulation is
584 E.A. Piccione et al.

advanced proximally does not always imply segmental usually less than 10 %, of patients have a slight lymphocytic
demyelination since primary axonal degeneration may mani- CSF pleocytosis greater than 10 cells/mm. GBS that follows
fest with conduction block before the completion of Wallerian Lyme or HIV infection often has a more prominent pleocyto-
degeneration [121]; and (3) although low distal CMAP sis that reflects a concurrent meningeal reaction [26, 122].
amplitudes imply almost always axonal loss, a severe distal Therefore, the presence of cells in the CSF certainly does not
demyelinative conduction block may mimic axonal degen- exclude the diagnosis, but other infectious disorders, such as
eration and shows improvement of CMAP over a short period Lyme and HIV [26, 122], or malignant conditions, such as
of time with good prognosis [94]. lymphoma [32], should be excluded.
Serial EDX studies are extremely useful in GBS for the
accurate diagnosis and prognosis of GBS. The disorder often
Antiganglioside Antibodies
evolves over several days to weeks, and a single early EDX
study and before the illness reaches its nadir may be mislead- Gangliosides are a large family of glycosphingolipids, predom-
ing. This lone study may miss the pathological changes that inantly distributed on the cell-surface membrane. Although
may have not been completed including Wallerian degenera- antibodies against many of these gangliosides have been
tion and sometimes rapid remyelination. Also, signs of seg- detected in sera of GBS patients, including LM1, GM1, GM1b,
mental demyelination are most evident during the third and GM2, GD1a, GalNAc-GD1a, GD1b, GD2, GD3, GT1a, and
fourth weeks of illness [95]. These serial EDX studies are GQ1b, the pathological significance of some of these antibod-
also mandatory for proper diagnosis and classification of
ies is not known. In addition, most of these antibodies are found
GBS subtypes (AIDP, AMAN, and AMSAN). In many cases, in subgroups of GBS patients. Antibodies to GD3, GT1a, and
the relative contributions of primary demyelination and GQ1b are often seen in high percentage of patients with GBS
axonal degeneration, or a combination of the two, cannot be associated with ophthalmoplegia, and antibodies to GQ1b are
determined with any certainty except if EDX studies are per- detected in 95 % of patients with MFS [123]. Antibodies to
formed many weeks after the onset of disease and corrobo- GM1, GM1b, GD1a, or GalNAc-GD1a are associated with
rated by the outcome. about 50 % of patients with AMAN or axonal variants of GBS
[78]. When strict criteria for GBS subtypes are used, IgG
autoantibodies against GM1 or GD1a are associated with
Cerebrospinal Fluid Studies AMAN, AMSAN, and acute motor-conduction-block neurop-
athy (see below), but not with AIDP. No specific ganglioside
Typically, the CSF protein level is elevated in the majority of antibody appears to be associated with AIDP, the prototypical
patients at some time during the course of the illness. The pro- and most common form of GBS in North America and Europe.
tein concentration is elevated in only 50 % of patients during This explains why these ganglioside antibodies are not clini-
the first week of illness and is elevated in 75 % by the third cally useful in clinical practice in these countries.
week [2]. Usually, the protein level peaks in the second or
third weeks of the illness followed by a slow decline towards
normal that may take several months. The cause of increased Imaging Studies
CSF protein is not known but presumably results from abnor-
Magnetic resonance imaging (MRI) is most useful in exclud-
malities in the blood-CSF barrier due to inflammation at the
ing central nervous system disorders which may mimic GBS
level of the spinal nerve roots. Patients with GBS and excep-
in their presentations. This includes MRI of the brain to rule
tionally high protein levels (e.g., 1,500 mg/dL) may develop
out brainstem pathology and MRI of the cervical and tho-
papilledema and symptoms of pseudotumor cerebri. Patients
racic spine to exclude cord compression or transverse myeli-
with AMAN and AMSAN also tend to have elevated CSF pro-
tis. MRI of the lumbar spine, however, is often abnormal and
tein levels, but the frequency of this finding and the protein
shows nerve root enhancement of the cauda equina with gad-
concentration is usually lower compared to patients with
olinium. This occurs in up to 80–90 % of patients particu-
AIDP; normal values are not unusual. There is also correlation
larly in children and in patients with severe weakness and
between the presence of demyelination on EDX studies and
severe leg and back pain (Fig. 28.3) [124, 125]. Occasionally,
the CSF protein concentration during the first 2 weeks of ill-
the facial nerves may also enhance with gadolinium in GBS
ness [100]. There is no apparent correlation between the CSF
patients with facial palsies [126].
protein level and clinical findings or outcome.
The increase in CSF protein is not usually associated with
a cellular response. This “cyto-albuminologic dissociation” Other Laboratory Studies
was observed first by Guillain-Barré and Strohl in their first
cases and made the disease credible by differentiating it Routine laboratory studies are usually normal in patients
from a number of febrile paralytic disorders, particularly with GBS. The erythrocyte sedimentation rate or liver
poliomyelitis [1]. However, in most large series, minorities, function studies are infrequently elevated, although these
28 Guillain-Barré Syndrome and Related Disorders 585

Fig. 28.3 MRI of lumbar spine in a 4 year old with GBS showing enhancement of cauda equina. T1 weighted image (left panel) is normal while
T1 weighted image following contrast shows enhancement of nerve roots (white arrow, right panel)

findings most likely reflect a recent, preceding infectious ill- Table 28.6 Differential diagnosis of Guillain-Barré syndrome
ness and have little diagnostic utility. Viral antibody titers, Peripheral neuropathies
particularly EBV and CMV, may be increased and thus help Toxic neuropathies
to identify the triggering infectious agent in individual cases. Heavy metals—arsenic, lead, thallium, gold
Prior infection with C. jejuni may be confirmed by detecting Medications—vincristine, disulfiram, nitrofurantoin, isoniazid
elevated serum IgM antibodies or culturing the bacteria from Organophosphate poisoning
the stool [19]. Hexacarbon (glue-sniffer’s neuropathy)
An HIV titer should be obtained in patients with GBS Acute intermittent porphyria
who have CSF pleocytosis, risk factors for HIV or reside in Vasculitic neuropathy
geographic regions where AIDS is prevalent. Urine porphy- Poliomyelitis
Diphtheria
rin screen, heavy metal testing, and Lyme titer may be indi-
Tick paralysis
cated in selected cases but are rarely necessary. Stool culture
Lyme disease
and serum titers for C. botulinum and anti-acetylcholine
Critical illness polyneuropathy
receptor antibodies are helpful in patients when the ocular- Polyradiculopathies and ganglionopathies
pharyngeal-brachial variant is considered or when electro- Carcinomatous or lymphomatous meningitis
physiological studies are consistent with a disorder of Acute sensory neuronopathy syndrome
neuromuscular transmission. Creatine kinase (CK) may be Disorders of neuromuscular transmission
slightly elevated, particularly in patients with muscle pain Botulism
and tenderness [63]. A very high serum CK level distin- Myasthenia gravis
guishes GBS from rhabdomyolysis or acute myopathies. Hypermagnesemia
Severe electrolyte imbalance may cause generalized weak- Antibiotic-induced paralysis
ness that rarely mimics GBS, and levels of magnesium, Snake envenomations
phosphorus, and potassium should be checked. Myopathies
Polymyositis
Other acute myopathies, e.g., drug induced
Differential Diagnosis Metabolic abnormalities
Hypokalemia
Hypophosphatemia
Acute GBS is easily recognized in typical cases, but unusual
Central nervous system disorders
presentations expand the differential diagnosis to many other
Basilar artery thrombosis with brainstem infarction
central nervous system and neuromuscular diseases
Locked-in syndrome
(Table 28.6). With several subtypes and variant syndromes Brainstem encephalomyelitis
(see below), GBS may mimic a variety of neurological disor- Transverse myelitis
ders [127]. Careful history and examination, coupled with Acute necrotic myelopathy
cautious interpretation of diagnostic testing, is often neces- Cervical cord or foramen magnum neoplastic compression
sary for accurate diagnosis. The first step is to establish that Hysteria
the clinical features are a consequence of a peripheral nerve Malingering
condition.
586 E.A. Piccione et al.

Acute Peripheral Neuropathies and Poliomyelitis progressive polyneuropathy [134]. Focal or multifocal onset,
severe pain, lack of diaphragmatic weakness or cranial nerve
Apart for GBS, the majority of acute peripheral neuropathies involvement, and electrophysiological features of a multifo-
are toxic in nature. Acute toxic neuropathies are axonal and cal axonopathy distinguish acute vasculitic neuropathy from
evolve in a subacute or chronic fashion. There are numerous GBS in most cases. Furthermore, the CSF protein level is
environmental, industrial (heavy metals), and occupational normal in the former condition. The diagnosis is established
toxins that cause a neuropathy, resembling GBS, following by pathologic evidence of vasculitis on biopsy material.
an acute exposure, including if a history of ingestion is lack- Nonsystemic vasculitic neuropathy is generally an indolent
ing. Acute arsenic poisoning may have a presentation that is condition that is rarely mistaken for GBS.
indistinguishable from GBS and AIDP. The EDX studies Lyme disease, a tick-borne illness, may be a consideration
may show findings of acquired demyelinating polyneuro- in cases of GBS presenting with facial diplegia or when there
pathy, which when repeated, convert to a dying-back neu- is a CSF pleocytosis. However, as already noted, most cases
ropathy [128]. Thallium, lead, n-hexane (glue-sniffers of Lyme neuropathy are characterized by chronic, slowly
neuropathy), and organophosphate poisoning are other progressive, distal sensory loss or an asymmetric, painful
examples of acute toxic neuropathies. In most instances, polyradiculopathy.
intoxication is heralded by gastrointestinal symptoms, and Poliomyelitis, once the most common cause of acute
usually there is involvement of other organ systems, skin paralysis in the world, is now a rarity except in few underde-
lesions, alopecia, and encephalopathy, coma, or other fea- veloped countries (see Chap. 19). The condition is most
tures of central nervous system toxicity. Acute toxic neurop- commonly contracted by non-vaccinated individuals after
athies are distinguished from GBS by the history of preceding exposure to infants who recently were vaccinated against
toxic ingestion and by detecting suspected toxins in the the poliovirus. A number of other viruses, typically the
serum or urine. Acute demyelinating neuropathies mimick- enteroviruses such as the West Nile virus, may produce an
ing GBS have been linked to certain medications, such as identical poliomyelitis syndrome and are a more common
amiodarone, perhexiline, and gold therapy for rheumatoid cause of acute motor neuronopathy simulating GBS.
arthritis. An acute, rapidly progressive neuropathy, similar to Affected individuals have a febrile illness, usually a gastro-
GBS, has been described in alcoholics [129, 130]. These enteritis, followed by a paralytic phase 7–14 days later. The
patients invariably have a long-standing history of alcohol neurologic syndrome begins with fever, headache, and neck
abuse prior to onset of the acute neuropathy. Most develop stiffness, followed by muscle pain, asymmetric flaccid limb
progressive generalized weakness, severe distal sensory loss, paralysis, and fasciculations, and reaches a nadir within
and areflexia over days to weeks. The condition is distin- 4 weeks. Mild confusion may occur early in the illness.
guished from GBS by a normal CSF protein concentration Diaphragmatic and oropharyngeal weakness are common
and axonal features on EDX studies. but the extraocular muscles and sensory functions are
Patients with acute intermittent porphyria (AIP) may spared. The CSF shows a lymphocytic pleocytosis and a
develop a neuropathy that resembles GBS [131–133]. A normal or mildly elevated protein concentration, in contrast
variety of medications or infections may trigger an acute to GBS. Similarly, nerve conduction studies in poliomyelitis
attack. Initial symptoms include vomiting, constipation, and show reduced or absent motor amplitudes with normal con-
abdominal pain. Seizures occur in 10–20 % of cases and duction velocities and no conduction block. Sensory poten-
delirium or other psychiatric symptoms occur in most. The tials are normal. Fibrillations are prominent in weak muscles
weakness is symmetric and begins in proximal muscles of early in poliomyelitis. Culture of the poliovirus from the
the arms, but widespread weakness develops in most as the pharynx or stool or detection of elevated antibodies directed
syndrome progresses. Hypertension, arrhythmias, or other against poliovirus with acute and convalescent sera estab-
features of dysautonomia are common. The cranial nerves lishes the diagnosis.
are typically spared. EMG shows an axonopathy rather than During the West Nile encephalitis epidemic in North
demyelination, thus differentiating this condition from typi- America in the late 1990s and early 2000s, many patients
cal GBS. Increased urinary excretion of delta-aminolevulinic with weakness were diagnosed mistakenly as GBS. Upon
acid and porphobilinogen during an acute attack of AIP further studies, it was clear that these were cases of West
establishes the diagnosis. Nile-induced poliomyelitis with evidence of anterior horn
Neuropathy is a common complication of systemic vascu- cell damage [135, 136]. When motor weakness occurs in
litis and usually evolves in a subacute fashion; rarely, acute West Nile, it may be asymmetric with paralysis of one limb
mononeuritis multiplex may have a fulminant course that (monoparesis) or fairly symmetric affecting four limbs
simulates an acute polyneuropathy. Polyarteritis nodosa, and (quadriparesis), with or without brainstem involvement and
hepatitis B or C-associated vasculitis Churg-Strauss syn- respiratory failure. EDX studies also reveal normal SNAPs,
drome are the vasculitides most likely to cause a rapidly low-amplitude CMAPs recorded from weak muscles, signs
28 Guillain-Barré Syndrome and Related Disorders 587

of diffuse active denervation (including the paraspinal regional variants of GBS (see Chap. 50). Food-borne botu-
muscles), and generalized or focal loss of motor units [137]. lism usually begins hours to days after the ingestion of the
The pathology is consistent with poliomyelitis with identified neurotoxin produced by Clostridium botulinum types A, B,
neuronal loss, perivascular chronic inflammation, and micro- or E by way of contaminated food. Nausea and vomiting are
glial proliferation in the ventral horns of the spinal cord, followed by constipation and neurological symptoms.
especially in the cervical and lumbar segments [138]. Blurred vision is an early complaint. Initial findings include
Diphtheria is also a rare cause of acute polyneuropathy in dilated pupils in most patients, with paralysis of accommo-
developed countries because of effective vaccination pro- dation, ptosis, and oropharyngeal weakness. Diaphragmatic
grams. It is also reported in closed communities in countries weakness with ventilatory failure is common and may be
where diphtheria remains endemic despite prior vaccination more severe than limb weakness. In contrast to GBS, the
[139]. Infection with Corynebacterium diphtheria produces deep tendon reflexes are usually preserved. EDX studies
a febrile syndrome with severe pharyngitis, followed by pal- show reduced amplitudes of the motor potentials with an
atal weakness and descending paralysis that develops weeks incremental increase of the amplitude (usually >100 %
later. A membranous exudate over the tonsils and pharynx is above baseline) following high-frequency repetitive nerve
present in most cases, and cervical adenopathy may be stimulation, indicating a presynaptic neuromuscular junc-
prominent. Bulbar weakness is present in the majority of tion abnormality. The CSF is normal. Detection of botuli-
patients. Over half the patients develop paralysis of accom- num toxin in the serum, contaminated food source, or culture
modation. Symmetric limb weakness may be mild or severe of Clostridium botulinum from the stool confirms the
with a predilection for proximal muscles. There is general- diagnosis.
ized areflexia, minimal sensory loss, and no dysautonomia. In myasthenia gravis (MG), the slow onset of weakness,
The course is slower than GBS, with maximal paralysis prominent fluctuation, fatigue, and the regional pattern of
developing as long as 3 months after the onset of palatal involvement usually poses little difficulty distinguishing
weakness. The CSF profile demonstrates a cyto-albumino- these cases from GBS, but rarely patients with MG have a
logic dissociation, similar to GBS, and EDX studies show an fulminant course with rapidly progressive limb and respira-
acute demyelinating neuropathy. Differentiation from GBS tory muscle weakness resembling an ocular-pharyngeal-
may be impossible if the early facial involvement is not rec- brachial variant of GBS (see below) [143]. Although ptosis
ognized, but the low prevalence of diphtheria in developed occurs in a minority of patients with GBS and may be tran-
countries makes GBS a more likely cause of acute, general- siently responsive to edrophonium, though it does not
ized, areflexic paralysis. fatigue. Similarly, oropharyngeal weakness, nasal speech,
Critical illness polyneuropathy (CIP) was once frequently and hypophonia do not fluctuate in GBS patients. Preserved
mistaken for GBS in the intensive care setting (see Chap. deep tendon reflexes and lack of sensory symptoms or signs,
76). It is now recognized as a common cause of limb weak- dysautonomia, or an elevated CSF protein level are other
ness and failure to wean in ventilated patients in intensive features that differentiate MG from variant patterns of GBS.
care units (ICU). CIP is encountered most often in patients Patients with MG usually have transient improvement in
who have had sepsis and multiorgan failure [140–142]. strength following administration of edrophonium. EDX
Flaccid limb weakness, muscle atrophy, and generalized studies easily differentiate the two conditions; in MG, nerve
hypo- or areflexia are found in most patients. A small minor- conduction studies are normal and low-frequency repetitive
ity have facial weakness or ophthalmoparesis. Accurate sen- nerve stimulation recording from a clinically affected mus-
sory examination may be difficult in ventilated ICU patients, cle demonstrates a decrement (>10 %) of the amplitude
but most patients appear to have distal loss of all sensory characteristic of a postsynaptic neuromuscular junction
modalities. Dysautonomia does not occur. The CSF protein abnormality.
concentration is normal and EDX studies demonstrate axonal Tick paralysis causes rapidly progressive paralysis that
loss with diffuse denervation without demyelination. Critical perhaps simulates GBS more closely than any other condi-
illness myopathy and prolonged exposure to neuromuscular tion [144]. The illness is rare and affects mostly children in
blocking agents are other conditions that may simulate GBS the northwestern United States in the spring and summer. A
in the ICU. short prodrome characterized by fatigue, paresthesias, and
ataxia is followed by generalized, areflexic weakness that
occurs 3–5 days after attachment of the tick. The CSF is nor-
Disorders of the Neuromuscular Junction mal throughout the illness. The EDX studies show reduced
motor amplitudes without demyelinating features; sensory
Botulism is a rare condition that begins with cranial nerve studies are normal. The diagnosis is established by finding
dysfunction followed by generalized paralysis and can be the tick, usually located at the hairline, and removal is fol-
confused with the oropharyngeal or ophthalmoparetic lowed by rapid recovery.
588 E.A. Piccione et al.

Central Nervous System Disorders Table 28.7 Guidelines for the general management of patients with
Guillain-Barré syndrome
Occlusion of the basilar artery with pontine infarction may Measure vital capacity as indicated by rapidity of deterioration:
produce flaccid quadriparesis with ocular and bulbar findings. Vital capacity 12–15 mL/kg: intubate
The symptoms usually begin suddenly and often there is a Vital capacity 15–19 mL/kg: intubate if bulbar paralysis
history of preceding transient ischemic attacks. Deep tendon Incentive spirometry to prevent atelectasis
reflexes may be reduced at the initial evaluation although Bronchial clearing and assisted coughing
Chest X-ray examination weekly, or more often
hyperreflexia develops after a few days or weeks. Babinski
Biweekly serum albumin, sodium, BUN, calcium measurements
signs are usually present. Vertical eye movements are pre-
Urinalysis weekly
served and other cranial nerve findings may be present but
Pulmonary embolism prophylaxis: 5,000 U heparin every 12 h
are usually asymmetrical. Most patients with brainstem subcutaneously
stroke are somnolent or comatose because of involvement of Peristalsis checked
the ascending reticular activating system. Gastrointestinal bleeding prophylaxis: magnesium-containing
Acute cervical transverse myelitis may cause a rapidly antacid 30–120 mL or sucralfate
progressive quadriparesis. The detection of a spinal sensory Decubitus prophylaxis: frequent position changes; air-floating bed or
level on the trunk and upper motor neuron findings water mattress and skin care
No antibiotic prophylaxis; urine and pulmonary infections treated
(hyperreflexia, extensor plantar responses) differentiates this
with antibiotics after bacterial sensitivities available, unless septic
condition from GBS, but in the spinal shock stage of an acute Tube feeding when swallowing is impaired (start with continuously
myelopathy, flaccid limb weakness and areflexia simulate a administered fiber-enriched mixtures)
lower motor neuron condition. In the acute inflammatory Inquiries daily concerning pain, sleep, and hallucinosis; administra-
myelopathies (multiple sclerosis, neuromyelitis optica, or tion of adequate pain treatment
acute disseminated encephalomyelitis), weakness is often Limitation of antecubital phlebotomy if plasma exchange anticipated
asymmetric, bowel and bladder dysfunction is an early and Reprinted with permission from Ropper et al. [145]
prominent finding, and the cranial nerves are normal. There
is usually an inflammatory response with lymphocytes in the rial blood gases are not as helpful as respiratory mechanics
spinal fluid. Increased signal abnormalities on T2-weighted in monitoring the evolution of diaphragmatic weakness in
MRI or gadolinium enhancement of the cervical or thoracic GBS patients. Vital capacity (VC), tidal volume, and nega-
cord establish the diagnosis. tive inspiratory force are reasonably sensitive reflections of
Anxiety or a panic attack may be considered early in the diaphragmatic power, and progressive decline in these values
illness when paresthesias are the only symptom of emerging indicates impending mechanical respiratory failure and the
GBS and deep tendon reflexes may be preserved. These need for ventilatory support (Fig. 28.4) [146]. These mea-
patients may be labeled as “anxious” with symptoms attrib- sures should be obtained early on in the course and repeated
uted to hyperventilation and are often discharged from the as frequently as dictated by the clinical state (up to every
emergency room, only to return later with generalized and 4–6 h). Bulbar dysfunction including swallowing problems
diaphragmatic weakness. with difficulty in clearing secretions increases the odds of
needing ventilator support. In general, if the forced vital
capacity is less than 15–20 mL/kg, the maximum expiratory
Treatment and Management pressure is less than 30 cmH2O and the maximum inspiratory
pressure is less than 30 cmH2O, impending respiratory arrest
Supportive Care is present and intubation should be performed [148]. Also,
PCO2 above 48 mmHg or PO2 less than 56 mmHg on room
Most patients with GBS require admission to an intensive air are definite indications for intubation [2, 149].
care unit (ICU) under the care of physicians who are familiar Prediction for respiratory failure in patients with GBS is
with the medical complications that develop in paralyzed important in order to improve outcome and reduce mortality.
ICU patients (Table 28.7) [146, 147]. The timely and skillful Several studies have recently tried to answer this question.
management of medical problems is as important as immune Walgaard et al. found that patients who required ventilatory
therapy in the outcome of patients with GBS. support had facial and/or bulbar weakness, shorter days
Ventilatory failure is a central issue and should be antici- between onset of weakness and admission, and more limb
pated in any GBS patient with progressive limb or oropha- weakness (higher Medical Research Council sum score)
ryngeal weakness. About 15–30 % of patients with GBS will [65]. Sharshar et al. proposed that patients should be moni-
need ventilatory support [65, 147]. Atelectasis develops early tored in ICU setting if at least one of the following predic-
and leads to mild hypoxemia. Hypercarbia and hypoxemia is tors of respiratory failure is present: (1) time from onset to
a later finding as ventilatory failure advances; therefore, arte- admission of <7 days, (2) inability to cough, (3) inability to
28 Guillain-Barré Syndrome and Related Disorders 589

Fig. 28.4 Schematic diagram Vital capacity

of pathophysiologic events in (ml/kg)
patients with ventilatory Respiratory pathophysiology Normal Ventilatory management
failure and Guillain-Barré 65
syndrome, with corresponding 45
suggested management
Poor cough — secretions accumulate 30 Chest physical therapy
(Reprinted with permission
from Ropper AH [190]) 25
Sigh mechanism compromised — Incentive spirometry and deep breathing
atelectasis and hypoxia begin 20 to minimize ongoing atelectasis

Sigh lost — atelectasis and shunting 15 Elective intubation for positive-pressure venti-
lation; several high-volume breaths per minute

Hypoventilation 10 Positive-pressure ventilation to aid gas

exchange and prevent fatigue
Hypercapnia
Full ventilation
5

stand, (4) inability to lift the elbows, (5) inability to lift or enzyme inhibitors or beta-blocking agents. Short-acting
head, or (6) vital capacity <60 % of predicted. More than intravenous medications, such as nitroprusside or esmolol, are
85 % of patients with 4 out of these 6 predictors were intu- preferred for patients who have severe, labile hypertension
bated [150]. Moreover, Durand et al. found that the EDX is and require immediate therapy. Conversely, postural hypoten-
a predictor for mechanical ventilation. They found that the sion, often precipitated by only minor position changes, can
risk of respiratory failure was very low in GBS patients with be effectively treated with a bolus of intravenous saline or by
less than 55.6 % conduction block of the common peroneal placing the patient in the supine position. Norepinephrine and
nerve [151]. other sympathomimetic agents generally should be avoided
Incentive spirometry is useful in the early stages of the because of the risk of rebound hypertension, but vasopressors
illness to prevent atelectasis. Frequent suctioning and chest may be necessary for those with persistent supine hypoten-
physiotherapy minimize the accumulation of secretions and sion. Invasive procedures or cholinergic medications may
prevent aspiration and bronchopneumonia, but patients with trigger excessive vagal discharges (“vagal spells”) and pre-
moderate oropharyngeal weakness (e.g., those who cannot cipitate bradycardia, asystole, or other vagally mediated
safely swallow liquids) will probably require intubation for arrhythmias [153, 154]. These episodes are usually transient,
protection of the airway. Most patients with severe, ventila- but anti-arrhythmic medications (atropine) or cardiac pacing
tor-dependent GBS who have no improvement after 2 weeks may be necessary [154]. Micturitional disturbances are com-
require tracheostomy to secure long-term airway manage- mon and can be managed with intermittent catheterization or
ment, avoid tracheal stenosis, facilitate suctioning, and max- an indwelling catheter [147, 155].
imize patient comfort. However, tracheostomy can be Nosocomial infections are probably the most common
deferred for another week if pulmonary function tests show medical complication that develops in GBS patients in the
any significant improvement form baseline. Older patients ICU with pulmonary infections predominating [156]. Other
with preexisting pulmonary disease are more likely to require infections include urinary tract infections and central venous
tracheostomy [152]. catheters sepsis. Tracheitis and sinusitis are other consider-
Autonomic dysfunction is a well-recognized feature of ations in intubated patients who have a persistent fever and
GBS and a significant source of mortality. It is present in 70 % no apparent source of infection. Every effort should be made
of patients, but serious and potentially fatal dysautonomia to identify the organism to guide appropriate antibiotic ther-
occurs in 20 % of patients. Severe autonomic disturbances apy. Routine monitoring of the chest X-ray and sputum and
affect mainly patients with severe weakness and those with urine cultures are useful. However, bacterial colonization
respiratory failure. Many of the features of autonomic dys- occurs frequently, and patients should receive antibiotic ther-
function are self-limited and require no intervention. For apy only when there is clinical evidence of an infection;
example, resting tachycardia is common in GBS patients and inappropriate treatment only increases the risk of infection
does not require treatment except in those with active coro- with resistant pathogens. Although indwelling urinary cath-
nary artery disease and acute myocardial ischemia. eters are often necessary in GBS patients, the risk of coloni-
Hypertension often develops as a consequence of a procedure zation and infection increases after several days.
(e.g., suctioning or catheter placement) but is usually transient Immobilization that is associated with GBS predisposes to
and does not require therapy. Sustained high blood pressure deep venous thrombosis and pulmonary embolism.
(e.g., >180/95) may be managed with angiotensin-converting Subcutaneous heparin or intermittent pneumatic compression
590 E.A. Piccione et al.

boots should be used routinely, and chronic anticoagulation within the first 2 weeks of the illness. The North American
with warfarin may be considered for those who are bedbound study involved 245 patients randomized to receive plasma
or ventilator dependent for long periods. Low molecular exchange, 200–250 mL/kg over five sessions within 2 weeks,
weight heparin has become popular, but the value of neither or supportive care [159]. Treated patients improved more
the old nor new type of heparin has been established by a trial; rapidly and regained the ability to walk earlier (an average of
they are presumed from experiences in general medicine to be 53 days for the plasma exchange group vs. 85 days in
helpful. Although mucous plugging is probably the most com- untreated patients). Furthermore, those who required ventila-
mon cause of acute respiratory decompensation in ventilated tor assistance and were treated with plasma exchange weaned
patients with GBS, any unexplained episode of acute oxygen sooner than controls (24 vs. 48 days). Similar findings were
desaturation requires evaluation for pulmonary embolism. reported from French and Swedish trials [160, 161]. Severely
Patients who are intubated or have dysphagia due to affected patients with features that are associated with a poor
oropharyngeal weakness require nasogastric tube feedings to prognosis (see below) also benefited from treatment, but
maintain long-term nutritional support. A gastrostomy tube probably less so than others. The efficacy of plasma exchange
can be placed at the time of tracheostomy in patients with is reduced if therapy is initiated after 3 weeks from the onset
prolonged recovery. Hyperalimentation may be necessary in of symptoms [159, 162]. Plasma exchange is most effective
patients with an ileus. Neostigmine or erythromycin can be when started within the first 2 weeks of symptom onset [159],
effective to treat ileus [147]. Moreover, daily abdominal aus- but benefits are still seen if started within 30 days of symp-
cultation and monitoring of opioid administration should be tom onset [163]. Improvement may occur after as few as two
performed. Judicious intravenous hydration is essential exchanges in patients with mild GBS, but four exchanges,
because insensible fluid losses may be substantial, leading to performed approximately on alternate days, appear neces-
dehydration and exacerbating autonomic instability. sary in those with moderate or severe forms of the illness
Hyponatremia may develop, usually as a consequence of [164]. Adding more exchanges is not indicated, since six
inappropriate antidiuretic hormone secretion. Hyponatremia exchanges are not superior to four in severe GBS [163, 164].
is an independent indicator of poor prognosis [70]. A recent report of the therapeutics and technology assess-
Pain is a common symptom in patients with GBS and is ment subcommittee of the American Academy of Neurology
often underappreciated by the medical staff [61, 63]. found that plasmapheresis is effective for the treatment of
Narcotics are almost always needed to manage pain, and the moderate and severe GBS (class I studies, level A) and prob-
use of nonnarcotic, chronic analgesics often provides addi- ably effective in mild disease (level B) [165].
tional relief. Carbamazepine and gabapentin are usually suc- Patients treated with plasma exchange generally experi-
cessful in alleviating pain during the acute phase of GBS and ence few serious adverse effects. Treatment-related compli-
may be used for long-term management of neuropathic pain cations include pneumothorax at the time of placement of
[147]. An excellent alternative for severe pain in the back or central venous catheters, line infection with bacteremia or
legs is epidural analgesia [157]. Most patients benefit from sepsis, cardiac arrhythmias, hypotension from rapid fluid
early physical and occupational therapy [158]. For example, shifts, and excessive bleeding. In some patients, generally
passive range of motion of paralyzed joints prevents contrac- large men, the high volume of exchange necessary may be
tures, foot boards minimize the risk of foot drop and shorten- accomplished through antecubital veins, thus obviating the
ing of the Achilles tendon, and frequent turning and air risk of a central venous catheter. Plasma exchange is difficult
mattresses reduce the risk of skin breakdown and develop- to conduct in young children and patients with severe dysau-
ment of decubitus ulcers. Symptoms of anxiety and depres- tonomia, especially those with hypotension, or with active
sion are also common, occur at all stages of the illness, cardiac disease, coagulopathy, or hepatic failure. Plasma
and should not be overlooked. Those who are paralyzed, exchange is safe to perform in children and pregnant
intubated, and unable to communicate with their caregivers women.
are most likely to experience fear and helplessness. Intravenous immune globulin was introduced as an alter-
Communication boards allow patients to maintain a connec- native to plasma exchange because of its efficacy in other
tion with their families, nurses, and medical staff. Facilitating immune-mediated disorders, its relative safety, and ease of
contact with recovered GBS patients provides additional administration. A randomized trial comparing IVIG (400 mg/
psychological support. kg/day for 5 days) to plasma exchange in 150 patients with
GBS established that (1) IVIG is an effective therapy for
GBS, (2) the efficacy is comparable to plasma exchange, and
Immunotherapy (3) there was a low frequency of adverse effects [166]. A
larger, international, randomized, multicenter, controlled
Several large, randomized, controlled trials have demon- trial of 379 patients with GBS (the “Sandoglobulin trial”)
strated the benefits of plasma exchange when performed subsequently compared IVIG (400 mg/kg/day for 5 days),
28 Guillain-Barré Syndrome and Related Disorders 591

plasma exchange (50 mL/kg exchanges over 8–13 days), and used in most subsequent studies of IVIG in patients with
combined therapy. It established that IVIG and plasma GBS. A longer duration or higher dose of IVIG treatment in
exchange had equivalent efficacy and that plasma exchange patients with severe disease may be beneficial. Indeed,
followed by IVIG provided no additional benefit [167]. There Raphael et al. found that, in select patients on mechanical
was no difference in functional disability scores at 4 and ventilation, a 6-day course of IVIG (total dose 2.4 g/kg) is
48 weeks between IVIG, plasma exchange, and combined more beneficial than a 3-day treatment (total dose 1.2 g/kg)
therapy, nor was there any difference in secondary outcome with more rapid rate of recovery [172]. More recently,
measures (time required to wean from mechanical ventila- Kuitwaard et al. compared IgG level in serum before and
tion, number of days to recover ambulation, and the propor- 2 weeks after infusion with the standard dose of IVIG (total
tion of patients unable to walk after 48 weeks). These findings dose 2 g/kg) [173]. They identified a large variation of IgG
were subsequently confirmed by several studies and meta- levels at 2 weeks following the infusion of the same standard
analysis, despite the lack of placebo studies in IVIG [163, dose and a dose–response relationship. More significantly,
168, 169]. A recent report of the therapeutics and technology patients with slight or no increase in serum IgG at 2 weeks
assessment subcommittee of the American Academy of had more severe clinical deficit at nadir, and fewer were able
Neurology concurred also that there is strong evidence (level to walk at 6 months. An international study is currently
A) to support the use of IVIG in GBS which should be initi- assessing whether additional IVIG in patients who do not
ated during the first 2 weeks of disease onset [169]. Also, the show a meaningful rise in IVIG level is beneficial.
analysis concluded that the combination of plasmapheresis Approximately 10 % of GBS patients treated with plasma
and IVIG is probably not better than either treatment alone. exchange or IVIG relapse after initial treatment. This rate is
The beneficial immunomodulator effects of IVIG are equal with the use of plasma exchange or IVIG [167, 174].
complex and not completely understood, but probably The cause of these relapses is unknown but may be related to
include neutralization of proinflammatory cytokines (espe- persistence of active disease after completing therapy or a
cially tumor necrosis factor-alpha and interleukin-1 beta), rebound in antibody production. Patients with a more pro-
downregulation of pathogenic antibodies, modulation of tracted course may be at higher risk for a relapse, but no
Fc-receptor-mediated phagocytosis, inhibition of comple- other predictive factors have been identified [175].
ment deposition, and promotion of remyelination [36, 44]. Occasionally, a relapse may be triggered by an intercurrent
Headache is probably the most common side effect of infection or an ongoing CMV or EBV infection. A single
IVIG occurring in up to 16 % of patients [169]. It may be study indicated that a repeated course of IVIG administered
prevented by premedication with analgesics or corticoster- to patients who do not respond or relapse following the ini-
oids and by slowing the rate of infusion. Other minor com- tial treatment may be of some benefit [176], but this regimen
plications include transient fever, chills, and transient is currently being evaluated by a controlled study. A GBS
hypertension. Serious adverse effects are currently rare and relapse raises the concern of more chronic disorder, namely,
occur in less than 5 % of patients. These include serum sick- CIDP. Ruts and colleagues found recently that GBS patients
ness reaction, aseptic meningitis, acute renal tubular necrosis deteriorate more rapidly (15–27 days) while CIDP worsen
(possibly due to a high osmotic load), and a hypercoagulable much slower (31–63 days) [177]. Also, CIDP is the likely
state with risk of deep vein thrombosis, especially in nonam- diagnosis if patients diagnosed with GBS exhibit more than
bulatory patients, and myocardial infarction or stroke, espe- two treatment-related fluctuations.
cially in patients with risk factors for cardiovascular disease. The difficult issue of how to treat patients with severe
IVIG should not be administered to patients with known IgA GBS who have not improved with standard therapies remains
deficiency, a rare genetic trait, because of a high risk of not well clarified. The “Sandoglobulin trial” showed that a
developing an anaphylactic reaction. Transmission of HIV course of plasma exchange followed by IVIG is not better
has not been reported, and infection with hepatitis C virus than plasma exchange of IVG alone [167]. A repeated dose
has been reported during the 1990s but not since. Recent of IVIG has only been shown to be effective in a small study
improvement of IVIG manufacturing using nanofiltration or [176]. An international study is being conducted in assessing
caprylate (a saturated medium-chain fatty acid) has essen- the use of additional IVIG in unresponsive server GBS
tially eliminated the risk of viral transmission. IVIG can be patients or those who relapse.
administered safely to pregnant patients [170]. Because IVIG A discussion on GBS treatment cannot be completed
is generally well tolerated and easy to administer, it has become without addressing corticosteroids. Anecdotal reports indi-
the preferred therapy for GBS in the United States [171]. cated for decades that corticosteroids were beneficial to
The optimal IVIG dose needed for patients with GBS patients with GBS, but larger, prospective studies showed
remains somehow controversial. The dose of IVIG was set subsequently that oral and intravenous high-dose corticoster-
arbitrarily at 400 mg/kg/day for 5 days (total dose 2 g/kg) oids made no difference in outcome [178, 179]. There is also
based on its use in hematologic disorders. This dose was limited evidence suggesting that oral corticosteroids may
592 E.A. Piccione et al.

slow recovery from GBS [180]. In combination with ally always incomplete [90]; at 1-year follow-up, most have
intravenous immunoglobulin, intravenous methylpredniso- substantial residual motor deficits [187]. In contrast to
lone may have a short-term effect and hasten recovery but AMSAN, patient with AMAN have a prognosis which is
does not significantly affect the long-term outcome [181]. comparable to patients AIDP. This may be due to rapidly
The efficacy of other pharmacological agents is unknown. reversible immune-mediated changes at the nodes of Ranvier
A small randomized controlled trial demonstrated that inter- (conduction failure) that occur in some patients with AMAN
feron beta 1a (Rebif®) was not associated with significant or the selective degeneration and subsequent quick regenera-
clinical improvement [182]. A recent meta-analysis con- tion of intramuscular motor nerve terminals [87, 89, 188].
cluded that there are no beneficial effects on GBS from Neurologic disability advances steadily until a plateau is
brain-derived neurotrophic factor or cerebrospinal fluid reached. The plateau phase usually lasts several weeks but
filtration [183]. may be only a few days in mild cases or persist for months in
patients with quadriplegia and ventilator dependence. At the
time of the maximum deficit, approximately one-third of
Prognosis patients require assisted ventilation, almost half are wheel-
chair or bedbound, 7 % have trouble walking, and the remain-
The majority of patients with GBS have a rapidly progres- der are ambulatory [189]. Once recovery begins, improvement
sive course followed by a plateau phase of varying duration. follows a predictable course; patients who were quadripa-
Three-quarters of patients reach a nadir by 1 week and virtu- retic often recover to walk in a few months, although about
ally all (98 %) do so by 4 weeks (Fig. 28.5) [77, 184–186]. half have persistent symptoms at 1 year. An earlier study
Approximately 15 % of patients have a mild condition, reported that at 1-year follow-up, 62 % had recovered com-
remain ambulatory, and recover after a few weeks. pletely, 14 % could walk but not run, 9 % could not walk
Conversely, 5–20 % of patients have a fulminant course and without assistance, 4 % remained bedbound or ventilated,
develop flaccid quadriplegia, ventilator dependence, and and 8 % died [190]. In a more recent study, full recovery or
axonal degeneration, often within 2 days from the onset of minor deficits were observed in 41 % of patients in the first
symptoms [110, 187]. This group is often caused by axonal month, 71 % in the third month, 86 % in the sixth month, and
loss (AMSAN subtype); The recovery is delayed and virtu- 92 % by the first year [184].
Features that predicted a poor recovery (inability to walk
independently) in various studies include older age
45
(>60 years), history of preceding diarrheal illness, recent
CMV infection, fulminant and rapidly progressive course,
40 ventilator dependence, hyponatremia, peroneal nerve con-
Retrospective series
duction block, and greatly reduced CMAP mean amplitudes
(N = 153)
35 (<20 % of the lower limit of normal) or inexcitable nerves
[66, 70, 159, 191].
Several clinical scoring systems to predict prognosis have
30
been used in the past. The Erasmus University scales have
Number of patients

been validated. The scales uses the GBS disability score

25
[179] (Table 28.8) and the Medical Research sum (MRC)
score [166] (Table 28.9), as well as several simple and easily
20 obtainable clinical data. The Erasmus GBS Outcome Score
(EGOS) was developed based on a prognostic model that
15 uses easy-to-obtain patients’ clinical characteristics during

10 Table 28.8 GBS disability score

0 A healthy state
1 Minor symptoms and capable of running
5
2 Able to walk 10 m or more without
assistance but unable to run
0 3 Able to walk 10 m across an open space
<1 1–2 2–3 3–4 4–5 5–6 6–7 >7 with help
Onset to first improvement (weeks) 4 Bedridden or chairbound
5 Requiring assisted ventilation for at least
Fig. 28.5 Time from onset of the illness to onset of improvement (end
part of the day
of the plateau phase) in the Massachusetts General Hospital retrospec-
tive series. (Reprinted with permission from Ropper AH et al. [145]) 6 Dead
28 Guillain-Barré Syndrome and Related Disorders 593

the acute phase of illness to accurately predict the chance of 3 months, and 6 months. The mEGOS is advantageous
being able to walk independently at 6 months. The EGOS is because it can predict groups with poor prognosis early in the
based on age, diarrhea, and GBS disability score at 2 weeks disease when treatment is considered to be most effective. In
after hospital admission that accurately predicts the chance addition, the Erasmus respiratory insufficiency score was also
of being able to walk independently at 6 months [185]. A validated with specific parameters which predict mechanical
final score higher than four correlates with poor recovery ventilation at the time of hospital admission. These include the
(Table 28.10). The modified EGOS (mEGOS) model replaced time between onset of weakness and admission, the MRC sum
the GBS disability score by the more detailed MRC sum score, and presence or absence of facial and/or bulbar weak-
score [186]. It is also applicable at hospital admission as well ness (see Table 28.10) [65].
as 1 week after hospital admission (see Table 28.10). It is The mortality from GBS, once reported to be as high as
used to predict inability to walk independently at 4 weeks, 10–20 % [192, 193], has been reduced to 1–5 % in North
America and Europe, most likely because of the advent of
critical care units with experience in the management of this
Table 28.9 Medical Research Council (MRC) sum score disorder [194–196]. The predictors of death are similar to the
Sum of Medical Research Council scores of six muscle groups tested predictors of poor disability outcome [194].
bilaterally: Approximately 3–6 % of patients with typical GBS
Shoulder abductors 0–5 develop a chronic relapsing course consistent with CIDP.
Elbow flexors 0–5 These cases are referred to as acute-onset CIDP. There are
Wrist extensors 0–5 no distinctive features that allow early recognition of these
Hip flexors 0–5
patients; however, CIDP should be considered very likely in
Knee extensors 0–5
patients with GBS whose relapses reach nadir after 8 weeks
Foot dorsiflexors 0–5
or have more than two relapses [177]. Some patients with a
MRC sum score 60 (normal) to 0
(quadriplegic) progressive phase of 4–8 weeks and a monophasic course
Medical Research Council score of an individual muscle group ranges
have been labeled subacute inflammatory demyelinating
from 0 to 5: polyneuropathy (SIDP) [197]. These patients fall between
0 No visible contraction CIDP and a relapsing GBS. These patients often do not
1 Visible contraction without movement of the limb relapse and treatment could be completely tapered over sev-
2 Active movement of the limb, but not against gravity
3 Active movement against gravity over (almost) the full range
eral months. A few patients had bouts of recurrent GBS
4 Active movement against gravity and resistance completely remitting and separated by long asymptomatic
5 Normal power intervals [198, 199].

Table 28.10 Erasmus GBS outcome score and respiratory insufficiency score
Erasmus GBS Erasmus GBS respiratory
outcome score Modified Erasmus GBS outcome score insufficiency score
At day 14 of hospital At hospital At day 7 of hospital
Prognostic factors Categories admission admission admission At hospital admission
Age at onset <40 years 1 0 0
41–60 years 0.5 1 1
>60 years 0 2 2
Diarrhea during 4 weeks Absent 0 0 0
prior to onset Present 1 1 1
Time between onset of >7 days 0
weakness and admission 41–60 days 1
>60 days 2
Facial or bulbar weakness Present 1
Absent 0
MRC sum score 60–51 0 0 0
50–41 2 3 1
40–31 4 6 2
30–21 3
£20 4
£30 6 9
GBS disability score 0 or 1 1
2 2
3 3
594 E.A. Piccione et al.

Guillain-Barré Syndrome Variants Table 28.11 Clinical spectrum of the anti-GQ1b antibody syndrome
Frequency of anti-GQ1b
Miller Fisher Syndrome Disorder Clinical features Ab (%)
MFS Ataxia, areflexia, ~95
The triad of acute ophthalmoplegia, ataxia, and areflexia, ini- ophthalmoplegia
tially described by Fisher in 1956, has been recognized as a Ataxic GBS Ataxia, sensory loss and ~65
areflexia
variant of GBS on the basis of shared clinical features with
Bickerstaff Ataxia, ophthalmople- ~70
the typical disease and EDX findings indicating an acute sen- encephalitis gia, hyperreflexia, and
sory neuropathy [200]. Miller Fisher syndrome accounts for impaired consciousness
approximately 5 % of GBS cases in North America and GBS Weakness, sensory loss, ~25
Europe but may represent as high as 20–25 % of GBS patients areflexia, cranial
neuropathy
in Eastern Asia [201, 202]. In some patients, the illness pro-
gresses to generalized GBS that overtakes the other features
[184, 203].
Diplopia is usually the first symptom, followed by limb or motor nerve terminals and motor nerve terminal blockade
gait ataxia that appears within days. Additionally, there may [207, 208]. The ataxia is believed to be secondary to selective
be mild distal paresthesias, dysphagia, or mild proximal limb involvement of muscle spindle afferents [52, 205, 206].
weakness in up to one-third to one-half of cases. In some About 20 % of patients with Miller Fisher syndrome have
patients, frank GBS develops with respiratory failure requir- followed C. jejuni infection and 8 % followed H. Influenzae
ing ventilator support. In patients with the classical syn- infection [209, 210]. The majority of patients peak at a
drome, respiratory failure is, however, rare [201, 202]. median of 1 week and improvement starts at a median of
Unilateral or bilateral asymmetric abducens weakness is a 2 weeks [211]. Most patients are recovered completely by
common initial finding and often evolves to complete exter- 6 months.
nal ophthalmoplegia. Ptosis is present in the majority of Miller Fisher Syndrome (MFS) and Bickerstaff’s encepha-
patients but pupillary function is usually preserved (a small litis with variable CNS and PNS involvement are considered
proportion do have internal ophthalmoplegia). Ataxia typi- now part of a continuous clinical spectrum with a common
cally involves all the limbs and gait but may be asymmetric pathogenesis related to the presence of anti-GQ1b antibody.
early in the illness. Large amplitude, discoordinated, and Ataxia and ophthalmoplegia are common to both conditions.
poorly metricated limb movements are indistinguishable Impaired consciousness and upper motor neuron signs are
from a cerebellar efferent ataxia. The deep tendon reflexes more characteristic of Bickerstaff’s encephalitis. The current
are absent in all fully developed cases. The Fisher syndrome hypothesis is that this antibody reaches the brainstem via area
can be confused with brainstem lesions such as encephalitis postrema, attacking the reticular formation and corticospinal
or infarction, but the presence of other central nervous sys- tract, among other structures. Hyperreflexia and Babinski’s
tem features (confusion, seizures, alternating hemiparesis, sign are present in 1/3 of the Bickerstaff’s encephalitis patients.
Babinski signs, etc.) and normal electrophysiologic studies CSF albuminocytological dissociation occurs in around 25 %
in the latter conditions clarify the diagnosis. of patients during the first week of illness, increasing to 50 %
The CSF protein level may be elevated in Fisher syndrome in the second week. Pleocytosis is present in 30 % of cases,
but less frequently than in typical cases of GBS [201]. The much more frequently than in the Fisher syndrome (around
EDX findings are abnormal in half of the patients with absent 5 %). MRI detects CNS lesions (brainstem and cerebellum) in
or low-amplitude SNAPs or a sural spaing pattern. Motor con- 1/10 of the Bickerstaff’s encephalitis patients [205]. Elevated
duction abnormalities are rare [204]. In almost all patients anti-GQ1b antibody is seen in up to 70 % of patients with
(95–98 %) with Fisher syndrome studied, there has been ele- Bickerstaff’s encephalitis (see Table 28.11).
vated antiganglioside antibodies directed against the epitope Immunotherapy has been found to be effective only in ret-
GQ1b (Table 28.11) [51, 205]. The observation that paran- rospective studies [202, 212, 213]. IVIG slightly hastens the
odal regions of the oculomotor, trochlear, and abducens recovery of ophthalmoplegia and ataxia, but does not seem
nerves are enriched with GQ1b ganglioside supports a role of to influence patients’ outcomes, presumably because of the
anti-GQ1b antibodies in the pathogenesis of ophthalmople- good natural history of Fisher syndrome. However, plasma
gia. Indeed, patients with incomplete forms (acute ataxic neu- exchange or IVIG should be administered as early as possi-
ropathy and acute ophthalmoplegia), generalized GBS with ble when the disorder overlaps with GBS or Bickerstaff
ophthalmoplegia, and Bickerstaff’s encephalitis also display brainstem encephalitis, because these conditions may not
the antibody [51, 205, 206]. Sera from patients with anti- have as good a natural course as the Fisher syndrome [202].
GQ1b antibodies and Fisher syndrome induced rapid and Animal models of MFS with transference of GQ1b antibod-
reversible failure of release of acetylcholine from presynaptic ies have showed efficacy of C5 complement inhibitors as
28 Guillain-Barré Syndrome and Related Disorders 595

promising treatment. Clinical application in human being is Aspiration is a common complication and most require
yet to be reported [214, 215]. intubation for airway protection. The CSF protein concentra-
tion is usually slightly increased. About half of the patients
exhibit elevated anti-GT1a antibodies, perhaps reflecting an
Ataxic Variant (Acute Ataxic Neuropathy) immune attack that is restricted to nerves with that particular
epitope serving as an antigenic target [221]. Antibodies
In 1962, Richter quoted the term ataxic GBS and described against GQ1b are also present in around a third of patients
a patient with acute severe “cerebellar type ataxia” without [221]. Nerve conduction studies may demonstrate demyeli-
proprioceptive sensory loss or ophthalmoplegia [216]. This nating and axonal changes limited to the upper limbs. The
group of patients presents with a rapid-onset ataxia, hypo- blink reflexes are very useful and often show demyelinative
or areflexia, distal paresthesias, and CSF albuminocytolog- changes that are commensurate with the severity of facial
ical dissociation [206]. They have negative Romberg test paralysis. Some patients with the pharyngeal-cervical-bra-
with intact proprioception, and 65 % of them have elevated chial variant of GBS show low-amplitude distal CMAPs and
GQ1b antibodies (see Table 28.11). SNAPs are intact in SNAPs and partial motor conduction blocks which normal-
60 % and reduced or absent in the rest [206]. Clinically, this ized within 4 weeks [222]. This is consistent with reversible
variant is similar to the Miller Fisher syndrome, except for conduction failure in both motor and sensory fibers which
the lack of ophthalmoplegia and reduced occurrence of can account for a better prognosis and similar to what is
elevated GQ1b antibodies (65 % vs. 98 % in Miller Fisher observed in AMAN. In the rest of the patients, recovery may
syndrome). Another group of acute ataxic patients, labeled take months and many patients need a gastrostomy tube for
“acute sensory ataxic neuropathy”, has similar presentation nutritional support and a tracheostomy for airway manage-
but positive Romberg test and marked proprioceptive sen- ment. Case reports have shown improvement with IVIG or
sory loss [217, 218]. About 90 % of these patients have plasma exchange [223].
low-amplitude or absent SNAPs [206]. Antibodies against
the epitopes GQ1b or GD1b are present in about 50 % of
these patients. It is now likely that the ataxic GBS, origi- Multiple Cranial Neuropathy Variant
nally described by Richter, and the acute sensory axonal
neuropathy form a continuous spectrum and represent an This GBS variant is characterized by acute onset of multiple
incomplete form of the Miller Fisher syndrome with simi- cranial nerve dysfunction, multiple ocular motor nerve pal-
larly good prognosis. Some authors recently proposed the sies, and facial and bulbar dysfunction [224]. This form
terms “acute ataxic neuropathy” [206] or “acute sensory accounts for around 5 % of GBS patients in Taiwan [224].
axonopathy-ganglionopathy” to encompass both of these The findings are often due to involvement of individual cra-
disorders [219]. The main differential diagnoses of ataxic nial nerves, often bilaterally and symmetrically. This also
GBS are subacute paraneoplastic sensory neuronopathy helps distinguish this from the pharyngeal-cervical-brachial
(anti-Hu syndrome), Sjögren syndrome, pyridoxine intoxi- variant of GBS. Bilateral IX, X, and XI cranial nerve impair-
cation, and vitamin B12 and thiamine deficiency. Anecdotal ment, resulting in dysphagia, laryngopharyngeal discomfort,
reports have shown improvement with IVIG or plasma and slurred speech, is the initial symptom in most cases
exchange [206]. [203]. The second most common mode of presentation is
facial nerve palsy, which is usually bilateral and of the
peripheral type [223]. Complete or partial bilateral extraocu-
Pharyngeal-Cervical-Brachial Variant lar nerve palsies may later develop. Although not initially
present, within 2–3 weeks most patients will develop sen-
A regional pattern of weakness of the cervical, brachial, and sory symptoms and limb weakness. Areflexia is usually
oropharyngeal muscles exclusively is a rare variant of GBS present.
[143, 220]. The clinical picture is characterized by a recent CSF analysis shows the characteristic albuminocytologic
history of viral illness followed by severe weakness limited dissociation in half of the patients in the first week after dis-
to pharyngeal and neck muscles at the onset, with spread to ease onset, a somewhat higher rate and earlier occurrence
the arms and legs only after several weeks. However, upper than that seen in typical GBS [223]. Most case series report
limb weakness may sometimes precede the dysphagia. abnormalities in motor and sensory conduction velocities
Muscle power, reflexes, and sensation are entirely spared in and abnormal F-wave responses. The characteristic rapid,
the legs. Facial weakness and respiratory failure also may progressive course with respiratory paralysis makes early
occur, thus simulating a disorder of neuromuscular transmis- recognition and prompt treatment very important. IVIG was
sion. Curiously, ptosis is almost universal, further emulating effective in most case series and this is considered the pre-
myasthenia gravis [143, 184]. Ophthalmoparesis is rare. ferred therapy [223, 224].
596 E.A. Piccione et al.

Facial Diplegia with Paresthesias tendon reflexes after several weeks. Routine nerve conduc-
tion studies are typically normal or show reduced SNAPs
A syndrome of acute-onset facial diplegia often associated particularly in patients with sensory ataxia. Specialized test-
with distal limb paresthesias is another GBS variant [225]. ing of autonomic functions (heart rate variability testing,
Other cranial nerve involvements, limb weakness, or ataxia quantitative axon reflex studies, tilt table testing) are abnor-
are absent. The majority of patients have hyporeflexia, while mal. The CSF protein concentration is usually mildly ele-
hyperreflexia has been described in this syndrome [226, vated. Combined sensory and autonomic GBS variants are
227]. More than 2/3 of them have a preceding infectious ill- probably common [219, 231].
ness. One-third of the patients have positive serology for a In order to diagnose this condition, one has to rule out a
recent CMV infection. All the patients had elevated CSF large number of disorders that may cause autonomic dys-
protein. Nerve conduction studies shows demyelinating function (cancer, multiple system atrophy, Parkinson’s dis-
changes in limb nerves in 60 % of patients. Favorable out- ease, amyloidosis, and others). Autoantibodies specific for
come occurred in the majority of patients and in some have nicotinic acetylcholine receptors in the autonomic ganglia
residual facial weakness [225]. are present in about 30 % of the paraneoplastic form and
50 % of the idiopathic autonomic ganglionopathies [232].
The seropositive group has less frequently a preceding viral
Paraparetic Variant illness but more frequently a subacute onset, abnormal pupil-
lary responses, sicca complex, and lower gastrointestinal
Another regional variant of GBS has features of isolated leg dysautonomia [233].
weakness and areflexia simulating a cauda equina or spinal This GBS variant characteristically progresses and then
cord syndrome [143]. The arms, ocular, facial, and oropha- plateaus after a few weeks, and approximately half the
ryngeal muscles are spared, and sphincteric function is nor- patients recover slowly after several months. There have
mal. Radicular leg pain is common and may be severe, but been case reports of improvement with immunomodulatory
other sensory features are more variable. The spinal fluid therapy, including plasmapheresis or infusion of IVIG
protein level is elevated in the majority. EDX studies show [234–236].
typical demyelinating features of GBS restricted to the legs.
MRI of the spinal cord and lumbar roots should be obtained
in these patients to exclude a lesion of the caudal spinal cord Other Possible GBS Variants
or cauda equina. Imaging may also show gadolinium
enhancement of the lumbosacral nerve roots, as also occurs A number of other peculiar constellations of neuropathic
in many typical GBS cases [124]. disorders that develops acutely, often after a minor infec-
tious illness, are possible variants of GBS. These conditions
begin acutely, are mostly bilateral in one region, evolve
Acute Pandysautonomia (Acute Autonomic over days or weeks, and are monophasic. Most are associ-
Neuropathy) ated with an elevated spinal fluid protein concentration
without a cellular response and with features of demyelina-
An acute autonomic neuropathy is thought to be another rare tion on EDX studies. These syndromes include acral par-
variant of GBS [184, 228, 229]. Gastrointestinal symptoms esthesias with diminished reflexes in either the arms or legs,
are commonly the initial features, namely, abdominal pain, abducens nerve palsies with distal paresthesias and hypo- or
vomiting, constipation, or diarrhea, all following a viral syn- areflexia, isolated ophthalmoplegia (e.g., asymmetric oculo-
drome. Gastroparesis or abdominal distention with an ileus motor nerve palsies), and bilateral foot drop with upper limb
may develop. Patients complain of lightheadedness due to paresthesias [237, 238]. A small fiber sensory neuropathy
orthostatic changes in blood pressure following positional was also described and considered by some authors to be a
changes, and in extreme forms, severe orthostatic hypoten- GBS variant [239, 240]. The outcome in these patients was
sion with recurrent syncope are seen. Additional manifesta- favorable.
tions that are acquired in the first week or two include erectile
dysfunction, urinary frequency, urgency, and retention; vaso-
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