verview and Recommendations

Background

 Guillain-Barre syndrome (GBS) is a group of acute immune-mediated

polyneuropathies most commonly presenting as acute inflammatory
demyelinating polyradiculoneuropathy (AIDP).

 Antecedent infections with organisms such as Campylobacter

jejuni, Mycoplasma pneumoniae, nonpolio enteroviruses, and Zika
virus are associated with development of GBS.

 Complications include respiratory failure (25-30%), autonomic nervous

system involvement, and sequelae from inactivity.

 The influenza vaccine is possibly associated with a small risk of GBS (1

per 1,000,000) and should not be given to patients who have had a prior
episode of GBS.

Evaluation

 The most common variant, AIDP, presents with acute progressive

ascending and generally symmetric weakness, pain, and paraesthesias
with hypo- or areflexia and sometimes bilateral cranial nerve
involvement. Features to identify on initial and subsequent evaluation
include respiratory difficulties from diaphramic weakness, and autonomic
nervous system dysfunction.

 Perform a lumbar puncture for cerebrospinal fluid (CSF) analysis in all

cases of suspected Guillain-Barre syndrome, which usually reveals
sterile fluid with a characteristic high concentration of protein and low or
normal white count.

 Consider an electrodiagnostic study to confirm the presence, pattern,

and severity of a peripheral demyelinating neuropathy, typically
demonstrating an early loss of proximal responses (F waves, H reflex)
followed by nerve conduction slowing or block.

 Major differential diagnoses include other acute peripheral neuropathies

and chronic inflammatory demyelinating polyradiculoneuropathy (CIPD)
among other conditions depending on subtype and presentation.

Management

 Monitor for a drop in vital capacity, autonomic dysfunction, and cardiac

arrhythmias as part of general medical measures.

 Consider an early transfer to an intensive care unit for prophylactic

intubation if there is a rapid progression of weakness with involvement of
the upper extremities, bulbar weakness, or autonomic dysfunction.
  Consider deep vein thrombosis (DVT) prophylaxis if the patient is not
ambulatory.

 Treatment:

o IV immunoglobin (IVIG) (usual dose is 2 g/kg given over 5 days) is

recommended primarily in adults who are unable to ambulate
independently within 2-4 weeks from onset of symptoms. (Strong
recommendation).

o Plasma exchange is recommended for adults requiring mechanical

ventilation or who are unable to ambulate independently (Strong
recommendation).

o IVIG and plasma exchange have similar recovery rates in adults with
Guillain-Barre syndrome (GBS) but plasma exchange has a greater
risk of side effects.

o Combination or sequential treatment with plasma exchange and IVIG

is not recommended (Strong recommendation).

o IVIG 1 g/kg may accelerate recovery rates in children but there is

limited comparative data with plasma exchange.

 Consider gabapentin to treat pain associated with GBS.

 A physical rehabilitation program (home or outpatient based) might

improve disability.

 Prognosis is good, with mortality related to complications of GBS rather

than the condition itself. However, minor residual neurologic defect is
common. The relapse rate is about 5%.

General Information
Description

 acute monophasic immune-mediated polyradiculoneuropathy(1, 2, 4)

Also called

 GBS

 Landry-Guillain-Barre syndrome

 Guillain-Barre-Strohl syndrome

 acute inflammatory polyneuropathy

 acute inflammatory demyelinating polyneuropathy (AIDP)

 acute motor axonal neuropathy

  acute motor and sensory axonal neuropathy

 acute autoimmune neuropathy

 idiopathic polyneuritis

Types

 clinical variants of GBS are based on type of fiber involved, mode of

injury, and presence or absence of altered consciousness(2, 4)

 acute inflammatory demyelinating polyradiculoneuropathy (AIDP), the

classic GBS variant, accounts for a majority of cases in Europe and
North America(1, 2)

 axonal variants (5% in North America and Europe, more common in

Northern China, Japan, and rest of America)

o acute motor and sensory axonal neuropathy (AMSAN)

 associated with GM1, GM1b, GD1a antiganglioside antibodies

 associated with Campylobacter jejuni infection

o acute motor axonal neuropathy (AMAN) ("Chinese paralytic illness")

 associated with GM1, GM1b, GD1a, GalNac-GD1a

antiganglioside antibodies

 may present with transient conduction block without axonal loss

(“acute motor conduction block neuropathy”) and with symmetric
proximal and distal weakness without sensory abnormalities
afterC. jejuni enteritis

 may have normal or brisk tendon reflexes

 associated with worse prognosis (more rapid progression of

weakness to earlier nadir with prolonged paralysis and respiratory
failure over a few days)
 Miller Fisher syndrome (MFS)(2, 4)

o accounts for fewer than 10% of cases in Western countries, more

common in eastern Asia (up to 25% in Japan)

o usually presents with 2 or more of the following triad:

ophthalmoplegia, ataxia, and/or areflexia

o associated with GQ1b, GT1a antibodies

o facial and lower cranial nerve involvement typical, but limb motor
weakness is not typical
 o overlap forms possible (Miller Fisher variant with limb weakness and
respiratory involvement)

 Bickerstaff brainstem encephalitis (BBE) is a variant of MFS

characterized by alteration in consciousness, paradoxic
hyperreflexia, ataxia, and ophthalmoparesis

o frequency is 10% of MFS variant

o antecedent infection present in 92%

o elevated cerebrospinal fluid (CSF) protein present in 59%

o anti-GQ1b antibody present in 66%

o magnetic resonance imaging (MRI) abnormalities present in

30%

 motor variants(2, 4)

o pharyngeal-cervical-brachial motor variant (more common)

 presents with ptosis, facial, pharyngeal, and neck flexor muscle

weakness which spreads to arms

 leg strength, sensation, and reflexes are spared

 presentation is similar to botulism

o paraparetic motor variant (less common)

 legs selectively affected with areflexia

 presentation similar to acute spinal cord lesion

 associated with back pain

 other rare variants include(2, 4)

o ptosis without ophthalmoplegia

o facial diplegia or sixth nerve palsies with paresthesias

o acute sensory neuropathy associated with GD1b antiganglioside

antibodies

o oropharyngeal syndrome associated with GT1a

Epidemiology
Who is most affected

 mean age of onset 40 years with bimodal peak(1, 4)

 o incidence rises with age

o minor peak in young adults

o peaks at age 20-24 years and 70-74 years (J Neurol Neurosurg

Psychiatry 1997 May;62(5):447 PDF)

 more common in men than women(2, 4)

o 1.3:1 male to female ratio (J Neurol Neurosurg Psychiatry 1997

May;62(5):447 PDF)

Incidence/Prevalence

 worldwide annual incidence reported to range from 1.1 to 1.8 per

100,000

o based on systematic review of 63 papers evaluating epidemiologic

data for Guillain-Barre syndrome

o most studies conducted in Europe and North America where rates

were similar

o annual incidence in children ranged from 0.34 to 1.34 per 100,000

o annual incidence increased with age after 50 years from 1.7 to 3.3
per 100,000

o Reference - Neuroepidemiology 2009;32(2):150

 incidence of GBS might be higher in winter than summer

o based on systematic review of cohort studies limited by significant

heterogeneity

o systematic review of 45 studies evaluating seasonal incidence rates

of GBS in 10,698 patients

o worldwide incidence of GBS significantly higher in winter than in

summer (incidence rate ratio 1.14, 95% CI 1.02-1.27) in analysis of
42 studies

 results limited by significant heterogeneity

 analysis excluded 3 studies in northern China with significantly

higher incidence in summer

o in subgroup analyses

 incidence higher in winter than summer in patients with

respiratory infection prior to GBS (incidence rate ratio 3.06, 95%
CI 1.84-5.11) in analysis of 5 studies in 208 patients
  no significant difference in seasonal incidence in patients with
diarrhea or Campylobacter jejuni infection in analysis of 6 studies
with 163 patients

o Reference - J Neurol Neurosurg Psychiatry 2015 Nov;86(11):1196

 age-standardized annual incidence 1.22 per 100,000 in women and 1.45

per 100,000 in men

o based on 228 incident cases of Guillain-Barre syndrome reported in

United Kingdom General Practice Research Database 1992-2000
with mean 1.8 million registered patients

o age-specific incidence rate per 100,000 person-years highest in men

aged 65-74 years (3.86) and women aged 75-84 years (2.54)

o Reference - Arch Intern Med 2006 Jun 26;166(12):1301

 estimated prevalence 47 per 100,000 persons in Europe in 2005 (Lancet

2008 Jun 14;371(9629):2039)

 mean annual incidence 2.27 per 100,000 children (mean age 5.4 years)
in northwest Iran 2001-2006, with unexpected high incidence in 2003
(BMC Neurol 2007 Aug 5;7:22 full-text)

 Miller Fisher variant less common and estimated to be 0.1 per 100,000 (2)

Likely risk factors

 Campylobacter jejuni infection associated with Guillain-Barre syndrome

(GBS)
o Campylobacter-associated GBS may occur after about 1 in 1,000
cases of C. jejuni infection

 based on extrapolation from incidence of C. jejuni infection and

incidence of GBS

 estimated that 1 of every 1,058 cases of C. jejuni infection is

followed by GBS

 higher risk (1 in 158 cases) estimated for C. jejuni serotype O:19

 Reference - Clin Microbiol Rev 1998 Jul;11(3):555 full-text

o C. jejuni infection associated with Guillain-Barre syndrome
(GBS)

 based on case-control studies

 103 patients with GBS (96 patients) or Miller Fisher syndrome (7

patients) were compared with 191 controls
 o 26% of cases and 2% of controls had evidence of recent C.
jejuni infection (70% of whom had diarrheal illness within
preceding 12 weeks) (odds ratio 16.6, 95% CI 5.6-49)

o C. jejuni-associated cases may have been more severe than

other cases

o Reference - N Engl J Med 1995 Nov 23;333(21):1374

 118 cases with GBS compared to 103 controls

o serologic evidence of recent C. jejuni infection in 36% cases

and 10% controls (odds ratio 5.3, 95% CI 2.4-12.5)

o Reference - Ann Intern Med 1993 Jun 15;118(12):947

o serologic evidence of C. jejuni infection reported in patients with GBS

 recent C. jejuni infection (positive C. jejuni serology and diarrheal

illness within prior 3 weeks) reported in 22 of 159 (14%)
consecutive patients with GBS (Neurology 2004 Aug
10;63(3):529)

 immunoglobulin G (IgG) antibodies to gangliosides GT1a and

GQ1b found in 6 of 7 patients with Miller Fisher syndrome (a
variant of GBS characterized by ophthalmoplegia, ataxia, and
areflexia), and all 6 had antibody cross-reactivity to
lipopolysaccharides from O:2 and O:23 strains of C. jejuni (Infect
Immun 1997 Oct;65(10):4038 PDF)

o review of GBS and C. jejuni infection can be found in Symp Ser Soc
Appl Microbiol 2001;(30):145S or in J Appl Microbiol 2001
Jun;90(s6):145S full-text

 antecedent surgery cited as a rare GBS trigger (Reference - J

Neuroimmunol 2016 Apr 15;293:17)

Possible risk factors

 influenza vaccination

o influenza vaccination associated with small risk for Guillain-Barre

syndrome (GBS) (about 1 per 1,000,000)
 possible very low risk of GBS after influenza vaccination

o 2 studies done within series of 2,173 incident hospital

admissions for GBS in Ontario, Canada, 1991-2004

o incidence of GBS about 14 cases per million person-years

o self-matched case series

  269 patients had GBS within 43 weeks of influenza
vaccination

 estimated relative incidence of GBS at 2-7 weeks after

vaccination was higher than 20-43 weeks after vaccination
(relative incidence 1.45, 95% CI 1.05-1.99)

o in time-series analysis, no increase in hospital admissions for

GBS following universal influenza immunization program in
2000

o Reference - Arch Intern Med 2006 Nov 13;166(20):2217 full-

text
 increase in GBS reported to be 1 per 1,000,000 after influenza
vaccination

o based on retrospective case study of combined 1992-1993

and 1993-1994 vaccine campaigns in United States

o 180 adults with GBS were interviewed with 19 patients having

influenza vaccine in the 6 weeks prior to onset

o GBS associated with vaccination (relative risk 1.7, 95% CI 1-

2.8, p = 0.04)

o risk of 1 additional case of GBS after influenza vaccination

about 1 per 1,000,000

o Reference - N Engl J Med 1998 Dec 17;339(25):1797 full-text,

editorial can be found in N Engl J Med 1998 Dec
17;339(25):1845

 501 reports of GBS following influenza vaccination reported from

1990 to 2003 (JAMA 2004 Nov 24;292(20):2478 full-text)

 risk for GBS from influenza vaccination was < 10 per million in
1976 and 1-2 per million doses in 1992-1994

o benefit clearly outweighs risk

o Reference - American Academy of Neurology Therapeutics

and Technology Assessment (Neurology 1999 May
12;52(8):1546)
o minimal or no risk of GBS reported with routine immunization
practice in United Kingdom (level 2 [mid-level] evidence)

 based on population surveillance study

 228 incident cases of GBS reported in United Kingdom General

Practice Research Database 1992-2000 with mean 1.8 million
registered patients
  age-standardized annual incidence 1.22 in women and 1.45 in
men

 age-specific incidence rate per 100,000 person-years highest in

men aged 65-74 years (3.86) and women aged 75-84 years
(2.54)

 only 7 cases (3.1%) had onset within 42 days of any

immunization, including 3 cases after influenza immunization

 adjusted relative risk during 42 days after immunization 1.03

(95% CI 0.48-2.18)

 Reference - Arch Intern Med 2006 Jun 26;166(12):1301 full-text

o pandemic (H1N1) 2009 vaccine associated with low risk of GBS

 based on 1 pooled analysis, 1 cohort study, and 1 case-control

study

 pooled analysis of 6 adverse event monitoring systems in United

States (Emerging Infections program, Medicare, Vaccine safety
Datalink, Post-licensure rapid immunization safety monitoring
network, Department of Defense, and Department of Veterans
Affairs) in about 23 million people vaccinated with influenza A
(H1N1) 2009 monovalent inactivated vaccines

o 77 cases of Guillain-Barre syndrome (GBS) occurred

o Influenza A (H1N1) 2009 monovalent inactivated vaccines

associated with increased risk of Guillain-Barre syndrome
(incidence rate ratio 2.35, 95% CI 1.42-4.01)

o vaccination associated with about 1.6 excess cases per

1,000,000 persons vaccinated

o Reference - Lancet 2013 Apr 27;381(9876):1461, editorial can

be found at Lancet 2013 Apr 27;381(9876):1437

 retrospective cohort study

o Quebec had 7.8 million residents in 2009-2010

o 4.4 million people (57%) had inactivated monovalent adjuvant

2009 pandemic influenza A (H1N1) 2009 vaccine between
October 2009 and March 2010

o 83 confirmed cases of GBS

o 42 (51%) patients with GBS had vaccination

 25 had disease onset ≤ 8 weeks after vaccination

(adjusted relative risk [RR] 1.8, 95% CI 1.12-2.87)
  19 had disease onset ≤ 4 weeks after vaccination
(adjusted RR 2.75, 95% CI 1.63-4.62)

o estimated risk of GBS attributable to vaccine about 2 per

million

o Reference - JAMA 2012 Jul 11;308(2):175 full-text, editorial

can be found in JAMA 2012 Jul 11;308(2):184 full-
text (correction can be found in JAMA 2012 Oct
3;308(13):1324)

 preliminary Centers for Disease Control and Prevention (CDC)

analysis of case-control study

o 529 reports of potential GBS from October 2009 to March

2010

o 326 cases met GBS case criteria, of whom 27 patients had

documentation of 2009 H1N1 vaccination in preceding 42
days, 274 did not receive vaccine, and others were unknown
or pending ascertainment

o estimated GBS incidence among hospitalized patients

 1.92 per 100,000 person-years among persons who had

pandemic (H1N1) 2009 vaccination

 1.21 per 100,000 person-years without vaccination

 estimated age-adjusted rate ratio 1.77 (95% CI 1.12-2.56)

o Reference - MMWR Morb Mortal Wkly Rep 2010 Jun

4;59(21):657 full-text
o pandemic influenza A (H1N1) 2009 vaccine not independently
associated with increased risk of GBS

 based on case-control study

 104 patients with GBS and variant Miller Fisher syndrome were
matched to 1 or more controls

 receipt of pandemic influenza A (H1N1) 2009 vaccine was

o associated with GBS in unadjusted analysis (odds ratio [OR]

2.8, 95% CI 1.3-6)

o not associated with increased risk of GBS after adjustment for

influenza-like illness and seasonal influenza vaccine (adjusted
OR 1, 95% CI 0.3-2.7)

 Reference - BMJ 2011 Jul 12;343:d3908 full-text, editorial can be

found in BMJ 2011 Jul 12;343:d4159
  meningococcal conjugate vaccine (Menactra)

o Menactra is meningococcal conjugate vaccine for serotypes A, C, Y,

and W135

o 15 confirmed cases of GBS reported in patients aged 11-19 years

within 6 weeks of Menactra vaccine (FDA MedWatch 2006 Oct 23),
details described in MMWR Morb Mortal Wkly Rep 2006 Oct
20;55(41):1120 full-text, correction can be found in MMWR Morb
Mortal Wkly Rep 2006 Nov 3;55(43):1177

o 8 cases of GBS following Menactra vaccine previously reported

(MMWR Morb Mortal Wkly Rep 2006 Apr 7;55(13):364 full-
text, MMWR Morb Mortal Wkly Rep 2005 Oct 14;54(40):1023 full-
text)

o over 2.5 million doses of Menactra distributed, so incidence of GBS

following Menactra lower than general population (Prescriber's Letter
2005 Nov;12(11):62)

 case reports of Guillain-Barre syndrome

o 2 cases of recurrent GBS after repeated tetanus toxoid immunization,

noted in American Academy of Neurology Therapeutics and
Technology Assessment (Neurology 1999 May 12;52(8):1546)

o 3 cases of GBS have been reported with isotretinoin; causal link not
established (BMJ 2004 Jun 26;328(7455):1537)

Factors not associated with increased risk

 no relationship between Guillain-Barre syndrome and

measles/mumps/rubella vaccination

o based on retrospective chart review

o retrospective study linking national hospital discharge register in

Finland from 1982 to 1986 with vaccination records of > 600,000
measles/mumps/rubella (MMR) vaccine recipients

o 189 children and adults met criteria for Guillain-Barre syndrome

(GBS) (annual incidence 0.93 per 100,000 population)

o no cases of GBS within 6 weeks after vaccination

o shortest time from MMR vaccination to GBS was 80 days (5-year-old

boy with gastroenteritis and respiratory infection 1 month prior to
GBS)

o 11 patients who had GBS after first MMR vaccination were

revaccinated within 6-48 months of recovery without relapses of GBS

o Reference - J Pediatr 2001 Feb;138(2):250

Etiology and Pathogenesis
Causes

 infections(1, 2, 4)

o two-thirds of Guillain-Barre patients have reported infections during 6

weeks prior to onset of syndrome

 Campylobacter jejuni documented in approximately one-third of

patients

o C. jejuni lipopolysaccharide shares epitopes with some

gangliosides

 closest association is with Miller Fisher syndrome (90% of

patients have antibodies against ganglioside GQ1b)

only small proportion of patients have bacteriologic

evidence of C. jejuni infection at time of disease
presentation but serologic evidence persists
 nonpolio enteroviruses

o based on cohort of 1,775 children < 15 years old with acute

flaccid paralysis in Pakistan

o 474 (27%) had isolation of nonpolio enteroviruses

o 62 (33%) of children with nonpolio enteroviruses had Guillain-

Barre syndrome

o Reference - BMC Infect Dis 2007 Feb 15;7:6 full-text

 Mycoplasma pneumoniae may be associated with Guillain-Barre

syndrome

 HIV infection, usually early in seroconversion or with induction

using highly active antiretroviral therapy (Reference - J Neurol Sci
2003 Apr 15;208(1-2):39)

 Zika virus infection is associated epidemiologically with GBS,

including reports of Zika virus RNA in patients with GBS

 reports of associations with other infections including

cytomegalovirus, Epstein-Barr virus, and parvovirus (Reference
- J Neurol Neurosurg Psychiatry 1988 May;51(5):613)

 influenza vaccination is possibly associated with small risk for Guillain-

Barre syndrome (about 1 per 1,000,000) (Reference - J Neurol
Neurosurg Psychiatry 1988 May;51(5):613)

Pathogenesis
  presumed autoimmune process, but precise pathogenesis for Guillain-
Barre syndrome and its variants unknown(4, 5)

o acute inflammatory demyelinating polyradiculoneuropathy (AIDP)

pathology associated with

 lymphocytic mononuclear cell infiltration and intense

macrophage-associated segmental demyelination

 absence of antiganglioside antibodies

o acute motor axonal neuropathy (AMAN) associated with

 limited lymphocytic infiltration and sparing of dorsal nerve roots,

dorsal root ganglia, and peripheral sensory nerves

 lengthening of node of Ranvier followed by recruitment of

macrophages to nodal region (early changes)

 immunoglobulin G (IgG) autoantibodies against GM1 or GD1a

gangliosides

o Miller Fisher syndrome associated with antibodies against GQ1b and

GT1a gangliosides

o molecular mimicry

 Campylobacter bacterial isolates from some patients have

lipooligosaccharides similar to certain gangliosides

o GM1 or GD1a (Guillain-Barre syndrome)

o GQ1b (patients with Miller Fisher syndrome)

History and Physical

History

Chief concern (CC)

 progressive weakness(1, 2, 4)

o usually symmetric (Pediatr Neurol 2011 Feb;44(2):110)

o progresses over period of days to weeks

o can be proximal, distal, or combination

o facial weakness often involved

o bulbar and ocular nerves less commonly involved

 sensory complaints common (but not sensory findings)(1, 2, 4)
 o numbness and paresthesia affect extremities and spread proximally

o pain may be prominent complaint in children

 rare symptoms (5%) include(4)

o urinary retention

o gastrointestinal complaints

 constipation

 gastric distention

 diarrhea

 fecal incontinence

 atypical presentation with facial diplegia and hyperreflexia can be found

in J Brachial Plex Peripher Nerve Inj 2007 Apr 10;2:9 full-text

History of present illness (HPI)

 symmetric ascending weakness, proximal and distal, which evolves over

days to weeks(1)

 nadir of weakness within 2 weeks in 50% of patients, and by 4 weeks in

90%(1, 4)

 hip pain preceding generalized weakness in 2-year-old with Guillain-

Barre syndrome in case report (BMJ 2001 Jan 20;322(7279):149 full-
text)

Past medical history (PMH)

 ask about prior respiratory illness(1, 4)

o upper respiratory infections without any specific organism identified is

most common

o 6% attributed to specific infection

 may include Epstein-Barr virus (mononucleosis or hepatitis) and

cytomegalovirus (CMV)

 if associated with HIV infection, may occur at time of

seroconversion or early in disease course

 bacterial infection rare

 ask about prior gastrointestinal illness (one-third of patients with Guillain-

Barre have documentation of Campylobacter jejuni infection)(1, 4)
Physical

General physical

 autonomic signs may be present(1, 4)

o tachycardia most common

o wide blood pressure changes (hypertension or postural hypotension)

o bradycardia

o cardiac arrhythmias

o neurogenic pulmonary edema

o changes in sweat

 respiratory signs include

o paradoxical breathing pattern due to diaphragmatic weakness

o shallow respirations

o Reference - Respir Care 2006 Sep;51(9):1016 PDF

HEENT

 may have unilateral or bilateral facial paresis(1, 4)

 ophthalmoplegia rare (reported in 5%)(4)

Neuro

 symmetric proximal and distal weakness(1, 4)

 areflexia (or decreased deep tendon reflexes)(1, 2, 4)

Diagnosis
Making the diagnosis

 diagnostic criteria for acute inflammatory demyelinating

polyradiculoneuropathy (AIDP) subtype of Guillain-Barre syndrome
o features strongly supporting diagnosis

 clinical features

o ascending muscle weakness with decreased or absent deep

tendon reflexes

o relative symmetry
 o mild sensory symptoms or signs

o cranial nerve involvement, especially bilateral weakness of

facial muscles

o autonomic dysfunction

o absence of fever at onset

o progression of symptoms over days to 4 weeks, then recovery

beginning within 4 weeks after progression ceases

 laboratory findings

o high concentration of protein in cerebrospinal fluid (CSF)

o white count in CSF < 10/mm3

o typical electrodiagnostic features of peripheral demyelinating

polyneuropathy including nerve conduction slowing or block

o features making diagnosis doubtful

 clinical features

o significant asymmetry of weakness

o persistence of bladder or bowel dysfunction

o bladder or bowel dysfunction at onset

o sharp sensory level on examination

 CSF findings

o > 50 mononuclear white blood cells/mm3

o presence of polymorphonuclear white blood cells

o features excluding diagnosis

 abnormal porphyrin metabolism

 recent diphtheria

 clinical picture consistent with lead neuropathy

 diagnosis of botulism, psychogenic paralysis, poliomyelitis, or

toxic neuropathy (including hexacarbon exposure)

 purely sensory syndrome, without weakness

o Reference - J Neurol Neurosurg Psychiatry 1998 Jan;64(1):74 full-

text
Differential diagnosis

 acute myelopathy (sensorimotor paralysis below affected spinal level)(2)

 myasthenia gravis (2)

 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (1, 2)

 infections

o Lyme disease (Acta Clin Belg 2009 May-Jun;64(3):225)

o HIV infection(2)

o acute poliomyelitis (epidemic occurrence or vaccination exposure

characterized by meningeal symptoms, fever, pure motor and usually
asymmetrical areflexic paralysis)(2)

o botulism (absent pupillary reflexes, bradycardia)(2)

o diphtheria(2)

o acute brainstem encephalitis(2)

o Coxiella burnetii infection (Q fever) (Arch Intern Med 2002 Mar

25;162(6):693)

 tick paralysis(2)

 acute intermittent porphyria (AIP) (abdominal pain, hyponatremia,

psychosis)(2)

 muscle disorders(1, 2)

o hypokalemia

o hypophosphatemia

o inflammatory myopathy

o acute rhabdomyolysis

o trichinosis

o periodic paralysis

 psychological cause of weakness(1, 2)

 toxins

o lead toxicity(1)

o inhalant abuse(2)
 o acute alcoholic polyneuropathy (Arch Neurol 1998 Oct;55(10):1329)

 medications

o suramin (IV drug used for African sleeping sickness and

onchocerciasis) associated with demyelinating neuropathy
resembling Guillain-Barre syndrome in 6 of 41 (15%) patients
(Muscle Nerve 1997 Jan;20(1):83)

o combination of colchicine and verapamil in case report of tetraparesis

(BMJ 2005 Sep 17;331(7517):613 full-text), correction can be found
in BMJ 2006 Apr 15;332(7546):882

o stavudine associated with potentially fatal lactic acidosis and rapidly

ascending neuromuscular weakness resembling Guillain-Barre
syndrome (FDA MedWatch 2002 Mar 29)

 critical illness neuropathy(2)

 basilar artery thromboembolism (locked-in state)(2)

Testing overview

 lumbar puncture (1, 2, 4)

o minimum studies on cerebrospinal fluid (CSF) include

 glucose

 protein

 cell count

 bacterial cultures

o CSF may be normal early on (during first few days); repeat lumbar
puncture if Guillain-Barre syndrome (GBS) strongly suspected

 electrodiagnostic studies including nerve conduction velocity (NCV) can

help confirm presence, pattern, and severity of neuropathy

 electrocardiogram (ECG) to evaluate for arrhythmia (autonomic

instability)(2)

 stool cultures for Campylobacter jejuni(2)

 nerve biopsy rarely indicated(2)

Blood tests

 antiganglioside antibodies may be present but do not generally affect

management
 o not present in patients with acute inflammatory demyelinating
polyradiculoneuropathy (AIDP)(5)

o acute motor axonal neuropathy (AMAN) associated with

immunoglobulin G (IgG) autoantibodies against GM1 or GD1a
gangliosides(5)

o Miller Fisher syndrome associated with antibodies against GQ1b and

GT1a gangliosides(5)
o GQ1b antibody levels in serum, but not CSF, may help
differentiate Miller-Fisher syndrome from other ophthalmologic
syndromes (level 2 [mid-level] evidence)

 based on diagnostic case-control study

 12 patients with Miller-Fisher syndrome, 21 patients with acute

ophthalmoplegia, and 13 patients with optic neuritis were
assessed for GQ1b antibody by enzyme-linked immunosorbent
assay (ELISA)

o samples were obtained within 4 weeks of symptom onset and

before immunotherapy

o all patients were diagnosed by clinical criteria

 for differentiating Miller-Fisher syndrome from other

ophthalmologic syndromes, GQ1b antibody ELISA with cutoff
50% had

o sensitivity 92% and specificity 97% in serum

o sensitivity 20% and specificity 100% in cerebrospinal fluid

(CSF)

 Reference - Neurology 2016 May 10;86(19):1780

Cerebrospinal fluid (CSF) analysis

 see Lumbar puncture (LP) for procedural information

 perform lumbar puncture for CSF analysis in all cases of Guillain-Barre

syndrome(4)

 albuminocytological dissociation(1, 4)

o increase in protein (may be albumin or immunoglobulin G) up to

1,800 mg/dL

o normal or low cell count (≤ 10 white cells in most cases)

o spinal fluid protein normal reported in 50% of patients in first week,

but this proportion decreases to 10%-25% when rechecked 1-2
 weeks later (N Engl J Med 2012 Jun 14;366(24):2294), correction
can be found in N Engl J Med 2012 Oct 25;367(17):1673

 diagnosis unlikely if > 50 cells/mm3 in CSF, especially 2 weeks after

symptom onset (consider early HIV infection, leptomeningeal
carcinomatosis, cytomegalovirus [CMV] polyradiculitis, sarcoidosis)(4)

 cerebrospinal fluid (CSF) analysis should be performed before treatment

with IV immunoglobulin (IVIG) which can cause aseptic meningitis (and
elevated CSF protein)(1)

Biopsy and pathology

 nerve biopsy rarely indicated(2)

 if biopsy done findings may include(2)

o acute inflammatory demyelinating polyradiculoneuropathy - multifocal

mononuclear cell infiltration throughout peripheral nervous system
with invasion and destruction of myelin sheaths

o acute motor axonal neuropathy - myelin sheath left intact with

macrophages invading nodes of Ranvier and may cause severe
degeneration of axon

o acute motor and sensory axonal neuropathy - macrophage infiltration

of perinodal space, but involvement of dorsal and ventral nerve roots
may also be affected

Pulmonary function tests

 assess respiratory function with vital capacity at baseline(1)

Other diagnostic testing

 electrodiagnostic study findings can help confirm presence, pattern, and

severity of neuropathy(1, 2, 4)

o often used in research to categorize diagnosis, but not required in all

diagnostic criteria (for example, Brighton criteria for use in resource-
poor settings) (N Engl J Med 2012 Jun 14;366(24):2294), correction
can be found in N Engl J Med 2012 Oct 25;367(17):1673

o may be normal in first week, and if so, should be repeated after 1-2
weeks

o nerve conduction velocities (NCV) abnormal in 85% of patients with

Guillain-Barre syndrome (GBS) if demyelination

 motor conduction studies abnormal earliest (may be partial motor-

conduction block) and may include
 o delayed F wave latencies (F waves are produced by
stimulating distally and recording impulse which is reflected
back; loss of F waves can be first sign of GBS)

o prolonged distal latencies

 sensory conduction studies become abnormal later

o electromyography (EMG) may become abnormal if axonal loss,

including reduced evoked amplitudes

Treatment
Treatment overview

 general medical measures

o monitor for drop in vital capacity, autonomic dysfunction, cardiac

arrhythmias

o consider early transfer to intensive care unit for prophylactic

intubation if rapid progression of weakness with involvement of upper
extremities, bulbar weakness, or autonomic dysfunction

o deep vein thrombosis (DVT) prophylaxis

 immunotherapy

o IV immunoglobulin (IVIG) usual dose is 2 g/kg given over 5 days

 IVIG recommended in adults (AAN Level A), mainly for patients

for patients unable to ambulate independently within 2 weeks
(AAN Level A, Class I) or 4 weeks (AAN Level B, Class II) from
onset of symptoms

 IVIG and plasma exchange have similar recovery rates in adults

with Guillain-Barre syndrome (GBS) (level 1 [likely reliable]
evidence)

 IVIG may accelerate recovery in children with GBS (level 2 [mid-

level] evidence) but limited comparative data with plasma
exchange in children

o plasma exchange

 plasma exchange recommended for patients with Guillain-Barre

syndrome (GBS) who require mechanical ventilation or are
unable to ambulate independently (AAN Level A, Class I) and
should be considered for milder GBS (AAN Level B, Class I)

 plasma exchange reduces time to recovery of walking in patients

with GBS (level 1 [likely reliable] evidence)
  albumin as replacement fluid during plasma exchange associated
with fewer adverse events than fresh frozen plasma (level 2 [mid-
level] evidence)

 plasma exchange associated with greater risk of side effects than

IVIG

o combination (AAN Level B) or sequential treatment (AAN Level A,

Class I) with plasma exchange and IVIG not recommended

 corticosteroids not recommended for treatment of patients with Guillain-

Barre syndrome (AAN Level A, Class I)

 for pain management

o gabapentin or carbamazepine may reduce pain in GBS (level 2 [mid-

level] evidence)

o gabapentin may be more effective than carbamazepine for pain (level

2 [mid-level] evidence)

Treatment setting

 all patients should ideally be observed in hospital until no evidence of

clinical progression(5)

o treat in critical care unit with continuous cardiac and respiratory

monitoring whenever feasible

o patients with very mild weakness who are able to walk independently
usually require only supportive care

 consider early transfer to intensive care unit for prophylactic intubation if

rapid progression of weakness with involvement of upper extremities,
bulbar weakness, or autonomic dysfunction(2)

 monitor regularly for(1, 2, 4)

o autonomic dysfunction with variation in pulse rate and blood pressure

o cardiac arrhythmias

o respiratory failure, signs of impending arrest include

 rapid decline of vital capacity to < 15 mL/kg age-adjusted ideal

body weight (more useful than blood gases or oxygen saturation
which may remain normal until breathing stops

 decreased negative inspiratory force to < 60 cm H2O

 weakness of neck muscles and inability to count out loud to 20

  mechanical ventilation may be indicated even if clinical respiratory
distress not apparent, if patient meets ≥ 1 major criterion or 2 minor
criteria(5)

o major criteria

 hypercarbia (partial pressure of arterial CO2 > 6.4 kilopascal [kPa]

[48 mm Hg])

 hypoxemia (partial pressure of arterial O2 on ambient air < 7.5

kPa [56 mm Hg])

 vital capacity < 15 mL/kg

o minor criteria

 inefficient cough

 impaired swallowing

 atelectasis

Medications

IV immunoglobulin (IVIG)

 possible mechanism of action include(4)

o interference with costimulatory molecules involved in antigen

presentation

o modulation of autoantibodies, cytokines and adhesion molecules

production, and macrophage Fc receptor

o disruption of complement activation and membrane attack complex

formation

 usual dose 2 g/kg administered over 2-5 days(4)

o likely no benefit for infusion over less than 5 days since most patients
are in hospital for > 2 days and infusions better tolerated if given over
5 days

suggested infusion regimen starts at 25-50 mL/hour for 30 minutes

o
and increases progressively by 50 mL/hour every 15-20 minutes up
to 150-200 mL/hour
 American Academy of Neurology (AAN) 2012 guideline for IV
immunoglobulin (IVIG) in treatment of neuromuscular disorders

o IVIG should be offered to treat Guillain-Barre syndrome in adults

(AAN Level A)
 o combination of IVIG and plasmapheresis should not be considered
for treating Guillain-Barre syndrome (AAN Level B)

o insufficient evidence to recommend methylprednisolone in

combination with IVIG (AAN Level U)

o insufficient evidence to support or refute efficacy of IVIG in children

with Guillain-Barre syndrome (AAN Level U)

o Reference - Neurology 2012 Mar 27;78(13):1009 PDF

 IV immunoglobulin and plasma exchange have similar recovery

rates in adults with Guillain-Barre syndrome (level 1 [likely reliable]
evidence)

o based on Cochrane review

o systematic review of 12 randomized or quasi-randomized trials

evaluating IV immunoglobulin (IVIG) in patients with Guillain-Barre
syndrome (GBS)

o no adequate trials found comparing IVIG vs. placebo in adults

o IVIG associated with shorter recovery time than supportive treatment

in 2 trials with 57 children

o comparing IVIG to plasma exchange (plasma exchange established

as effective for GBS in another Cochrane review)

 no significant differences in

o change in disability grade at 4 weeks in analysis of 5 trials

with 536 patients

o mortality in analysis of 7 trials with 623 patients

o adverse events attributed to treatment in analysis of 4 trials

with 388 patients

o relapse or treatment-related fluctuations in analysis of 3 trials

with 445 patients

 IVIG associated with lower discontinuation rate in analysis of 4

trials with 495 patients

o risk ratio 0.14 (95% CI 0.05-0.36)

o NNT 8-12 with discontinuation in 13% of plasma exchange

group

 multiple complications in 6.8% in IVIG group vs. 21.9% in plasma

exchange group (p = 0.015, NNT 7) in 1 trial with 147 patients
  data on children too limited to support subgroup analyses for
children

o IVIG after immunoabsorption significantly decreased disability at 4

weeks vs. immunoabsorption alone, but no significant difference at 1
year in 1 trial with 37 patients

o no significant difference in improvement in disability grade at 4 weeks

comparing

 IVIG after plasma exchange vs. plasma exchange alone in 1 trial

with 249 adults

 IVIG vs. immunoabsorption in 1 trial with 38 patients

 IVIG 2.4 g/kg vs. IVIG 1.2 g/kg in 1 trial with 39 adults

 standard IVIG dose over 2 days vs. 5 days in 1 trial with 49

children

o Reference - Cochrane Database Syst Rev 2014 Sep

19;(9):CD002063
 IVIG may not accelerate recovery in children with GBS (level 2 [mid-
level] evidence)

o based on small randomized trial

o 21 children with GBS and able to walk unaided for 5 meters were
randomized for IVIG 1 g/kg over 2 days vs. no treatment

 comparing IVIG vs. no treatment, improvement in main disability

score in 8 days vs. 32 days (p = 0.046)

o 51 children (including 5 from no treatment arm who progressed) with

GBS and inability to walk unaided for 5 meters were randomized to
IVIG 1 g/kg over 2 days vs. IVIG 0.4 g/kg over 5 days

 no significant difference in number of days to regain ability to walk

unaided (median 19 days vs. 13 days)

o Reference - Pediatrics 2005 Jul;116(1):8 full-text, editorial can be

found in Pediatrics 2005 Jul;116(1):226 full-text
 smaller increase in serum IgG levels 2 weeks after starting IVIG
associated with decreased improvement in clinical outcome at 6
months (level 2 [mid-level] evidence)

o based on cohort study

o 174 GBS patients who participated in 2 randomized trials evaluated 2

weeks after IVIG infusions

o mean increase in serum immunoglobulin G (IgG) 2 weeks after IVIg

7.8g/L +/- 5.6g/L.
 o rate of change in IgG associated with outcome (p = 0.022)

o compared with highest quartiles, lowest quartiles of change in IgG

associated with smaller improvement in clinical outcome (odds ratio
0.148, 95% CI 0.05-0.48)

o Reference - Ann Neurol 2009 Nov;66(5):597

 IVIG, but not plasmapheresis, may be associated with slightly faster

improvement of ophthalmoplegia or ataxia in patients with the
Miller Fisher syndrome, without effect on time to complete recovery
(level 2 [mid-level] evidence)

o based on retrospective cohort study

o 92 patients with Miller Fisher syndrome who had been treated with
IVIG (28 patients), plasmapheresis (23 patients), and no immune
treatment (41 patients) reviewed

o comparing IVIG vs. no treatment, amelioration of

 ophthalmoplegia in 12 days vs. 13.5 days (p = 0.04)

 ataxia in 8 days vs. 10 days (p = 0.027)

o no significant differences between groups for time to disappearances

of symptoms

o Reference - Neurology 2007 Apr 3;68(14):1144

 no randomized or nonrandomized trials identified to evaluate

immunomodulatory therapy for Miller Fisher syndrome and its clinical
variants in Cochrane review (Cochrane Database Syst Rev 2010 Jan
20;(1):CD004761)

 see Immune globulin for prescribing information

Corticosteroids

 corticosteroids not recommended for treatment of patients with Guillain-

Barre syndrome (AAN Level A, Class I)(3)
 oral corticosteroids may slow recovery in patients with Guillain-
Barre syndrome (level 2 [mid-level] evidence)

o based on Cochrane review of trials with methodologic limitations

o systematic review of 8 randomized or quasi-randomized trials

comparing corticosteroids vs. placebo or no treatment in 653 patients
with Guillain-Barre syndrome

o 5 trials evaluated oral corticosteroids (all had methodologic limitations

including no allocation concealment and/or small sample size)
 o all oral corticosteroid regimens consisted of equivalent of
prednisolone 40 mg/day for ≥ 2 weeks

o disability graded on 7-point scale (0 for healthy, 6 for dead)

o comparing oral corticosteroids to control

 oral corticosteroids associated with less improvement in disability

grade at 4 weeks (mean difference -0.82, 95% CI -1.47 to -0.17)
in analysis of 4 trials with 120 patients

 no significant differences in

o disability grade at 12 months in 1 trial with 40 patients

o mortality in analysis of 5 trials with 138 patients

o Reference - Cochrane Database Syst Rev 2016 Oct

24;(10):CD001446
 IV corticosteroids (alone or in combination with IV immunoglobulin)
do not appear to improve disability in patients with Guillain-Barre
syndrome (level 2 [mid-level] evidence)

o based on Cochrane review limited by clinical heterogeneity

o systematic review of 8 randomized or quasi-randomized trials

comparing corticosteroids vs. placebo or no treatment in 653 patients
with Guillain-Barre syndrome

o 3 trials evaluated IV methylprednisolone and 2 trials had data for

analysis

 1 trial evaluated methylprednisolone monotherapy and 1 trial

evaluated addition of IV methylprednisolone to IV immunoglobulin

 both gave methylprednisolone 500 mg/day IV for 5 days

o comparing IV methylprednisolone to control

 no significant difference in disability grade

o at 4 weeks in analysis of 2 trials with 467 patients

o at 6 months in analysis of 2 trials with 455 patients (consistent

results at 12 months in 2 trials with 431 patients)

 no significant difference in mortality in analysis of 2 trials with 467

patients

 IV methylprednisolone associated with

o increase in diabetes mellitus requiring insulin (risk ratio 2.21,

95% CI 1.19-4.12) in analysis of 2 trials with 467 patients
 o decrease in hypertension (risk ratio 0.15, 95% CI 0.05-0.41) in
analysis of 2 trials with 467 patients

o Reference - Cochrane Database Syst Rev 2016 Oct

24;(10):CD001446

Pain management

 limited evidence regarding pain management options in patients with

GBS
o gabapentin may reduce pain and may be more effective than
carbamazepine in patients with Guillain-Barre syndrome (level 2
[mid-level] evidence)

 based on Cochrane review with limited evidence

 systematic review of 3 randomized trials evaluating

pharmacologic treatments for pain in 277 patients with Guillain-
Barre syndrome

 all trials enrolled patients with acute phase Guillain-Barre

syndrome and had treatment duration ≥ 1 week

 gabapentin significantly reduced pain compared to

o placebo in 1 trial with 18 patients

o placebo or carbamazepine in 1 trial with 36 patients

 no significant difference in pain comparing methylprednisolone vs.

placebo in 1 trial with 223 patients (below)

 adverse effects not significantly different in smallest trial (18

patients) and not sufficiently reported in 2 other trials

 Reference - Cochrane Database Syst Rev 2015 Apr

9;(4):CD009950
o carbamazepine may reduce pain in GBS (level 2 [mid-level]
evidence)

 based on small randomized crossover trial

 12 patients aged 22-54 years with GBS in intensive care unit for
ventilatory support randomized to carbamazepine 100 mg
through nasogastric tube every 8 hours vs. placebo for 3 days

 patients switched treatments after 1-day washout period

 mean pain rating scale scores significantly decreased during

carbamazepine therapy vs. placebo (p < 0.001)

 Reference - Crit Care Med 2000 Mar;28(3):655

 o methylprednisolone may not reduce pain in GBS (level 2 [mid-
level] evidence)

 based on randomized trial with allocation concealment not stated

 223 patients (median age 50 years) with GBS randomized to

methylprednisolone 500 mg/day vs. placebo for 5 days and
followed for 4 weeks

 all patients also received IV immunoglobulin

 123 patients (55%) had pain at randomization

 no pain reported in 49% with methylprednisolone vs. 57% with

placebo (not significant)

 Reference - J Neurol 2007 Oct;254(10):1318

Experimental therapies

 pharmacological treatments other than corticosteroids, IV

immunoglobulin (IVIG), and plasma exchange have insufficient
evidence for GBS

o based on Cochrane review

o systematic review of 4 randomized trials evaluating pharmacological

treatments other than corticosteroids, IVIG, and plasma exchange in
109 patients with GBS

o trials were small and data could not be combined due to

heterogeneity of interventions

o Chinese herbal medicine tripterygium polyglycoside associated with

higher rate of improvement by ≥ 1 point in disability grade after 8
weeks (91%) compared to corticosteroids (62%) in 1 trial with 43
patients (p ≤ 0.05, NNT 4)

o no significant differences found in comparisons of

 interferon beta-1a vs. placebo in 1 trial with 13 patients

 brain-derived neurotrophic factor vs. placebo in 1 trial with 10

patients

 cerebrospinal fluid filtration vs. plasma exchange in 1 trial with 37

patients

o Reference - Cochrane Database Syst Rev 2013 Feb

28;(2):CD008630

 amantadine may not reduce fatigue in patients with Guillain-Barre

syndrome (level 2 [mid-level] evidence)
 o based on randomized crossover trial with inadequate statistical
power

o 80 patients with GBS and severe fatigue after at least 2 weeks were
randomized to amantadine vs. placebo in crossover trial

o 74 patients analyzed

o fatigue reduced prior to randomization

o no significant differences comparing amantadine with placebo for

fatigue, anxiety, depression, handicap, or quality of life

o mean change in fatigue severity scores favored amantadine but did

not reach statistical significance (p = 0.076)

o before unblinding, 75% patients wanted to continue amantadine

instead of placebo

o Reference - J Neurol Neurosurg Psychiatry 2006 Jan;77(1):61 full-

text

o no additional trials evaluating amantadine for fatigue in patients with

Guillain-Barre syndrome found in Cochrane review (Cochrane
Database Syst Rev 2014 Dec 18;(12):CD008146)

Procedures

Plasma exchange

 removal of 3-6 L of plasma over several hours and replacing it with

albumin (preferred) or fresh frozen plasma (less common)(4)

 requires large double-lumen catheter through subclavian, internal jugular,

or femoral venous access(4)

 monitor fluid intake and output, blood pressure, and pulse(4)

 contraindicated if patient hemodynamically unstable(4)

 American Academy of Neurology (AAN) recommendations on

plasmapheresis

o plasmapheresis established as effective and should be offered for

acute inflammatory demyelinating polyneuropathy/Guillain-Barre
syndrome (GBS) severe enough to require mechanical ventilation or
impair walking independently (AAN Level A, Class I)

o plasmapheresis probably effective and should be considered for

milder acute inflammatory demyelinating polyneuropathy/GBS (AAN
Level B, Class I)
 o there is insufficient evidence to demonstrate the superiority plasma
exchange versus IV immunoglobulin (IVIG)

o Reference - AAN evidence-based guideline update on

plasmapheresis in neurologic disorders (Neurology 2011 Jan
18;76(3):294 full-text)

 American Society for Apheresis (ASFA) recommendations

o therapeutic plasma exchange (TPE) can be used as first-line
therapy for Guillain-Barre syndrome (GBS) (ASFA Category I,
Grade 1A)

 based on systematic review of 19 randomized trials (with 1,770

patients), 9 case series (with 369 patients), and 10 case reports
(with 11 patients)

 suggested approach to TPE is 1-1.5 total plasma volumes (TPV)

using albumin as replacement fluid every other day for 5-6
treatments over 10-14 days

 Reference - American Society for Apheresis (ASFA) guideline on

use of therapeutic apheresis in clinical practice (J Clin Apher
2013 Jul;28(3):145)
o role of therapeutic plasma exchange (TPE) not established for
Guillain-Barre syndrome (GBS) after completed course of IVIG 2
g/kg (ASFA Category III, Grade 2C)

 based on systematic review of 1 case series (with 46 patients)

 suggested approach to TPE is 1-1.5 total plasma volumes (TPV)

using albumin as replacement fluid every other day for 5-6
treatments over 10-14 days

Reference - American Society for Apheresis (ASFA) guideline on

use of therapeutic apheresis in clinical practice (J Clin Apher
2013 Jul;28(3):145)
 plasma exchange for patients with Guillain-Barre syndrome reduces
time to recovery of walking and increases likelihood of full muscle
strength at 1 year (level 1 [likely reliable] evidence)

o based on Cochrane review

o systematic review of 6 randomized and 2 quasi-randomized trials

evaluating plasma exchange in patients with GBS

o no trial had blinding of patients (sham apheresis considered unethical

by all trial authors)

o no trial included children < 10 years old

o comparing plasma exchange to supportive treatment for various

outcomes
 no significant difference in mortality at 1 year in analysis of 6 trials
with 649 patients

 motor recovery

o median time to onset of motor recovery 6 days vs. 10 days (p

< 0.0001) in 1 trial with 220 patients

o increased recovery of full muscle strength at 1 year in analysis

of 5 trials with 404 patients

 risk ratio (RR) 1.24 (95% CI 1.07-1.45)

 NNT 4-26 with full muscle strength recovery in 55% in

supportive treatment group

 walking with aid

o median time to recovery of walking with aid

 30 days vs. 44 days (p < 0.01) in 1 trial with 220 patients

 12 days vs. 14 days (not significant) in 1 trial with 91

patients with mild GBS

o increased walking with aid at 4 weeks in analysis of 3 trials

with 349 patients

 RR 1.6 (95% CI 1.19-2.15)

 NNT 4-20 with 27% walking with aid at 4 weeks in

supportive treatment group

 walking without aid

o median time to recovery of walking without aid

 53 days vs. 85 days (p < 0.001) in 1 trial with 245 patients

 70 days vs. 111 days (p < 0.001) in 1 trial with 220

patients

o increased walking without aid at 4 weeks in analysis of 3 trials

with 349 patients

 RR 1.72 (95% CI 1.06-2.79)

 NNT 5-139 with 12% walking without aid at 4 weeks in

supportive treatment group

 decreased mechanical ventilation at 4 weeks in analysis of 5 trials

with 623 patients

o RR 0.53 (95% CI 0.39-0.74)

 o NNT 6-15 with ventilation at 4 weeks in 27% in supportive
treatment group

 increased relapse at 6-12 months in analysis of 6 trials with 649

patients, but results limited by lack of significant differences in
high-quality trials

o RR 2.89 (95% CI 1.05-7.93)

o NNH 12-1,667 with relapse in 1.2% in supportive treatment

group

o Reference - Cochrane Database Syst Rev 2012 Jul 11;(7):CD001798

 plasma exchange may shorten duration of mechanical ventilation
compared to IVIG in children with GBS and respiratory failure (level
2 [mid-level] evidence)

o based on small randomized trial

o 41 children with GBS requiring endotracheal mechanical ventilation

within 14 days of disease onset were randomized to plasma
exchange (1 volume/day for 5 days) vs. IVIG (0.4 g/kg/day for 5
days)

o comparing plasma exchange vs. IVIG

 median duration of mechanical ventilation 11 days vs. 13 days (p

= 0.037)

 median duration of intensive care unit stay 15 days vs. 16.5 days
(not significant)

 ability to walk 10 meters independently in 95.2% vs. 90% (not

significant)

o Reference - Crit Care 2011 Jul 11;15(4):R164 full-text, commentary

can be found in Crit Care 2011 Jul 28;15(4):174

 complications include(4)

o pneumothorax

o hypotension

o sepsis

o pulmonary embolism

o hemorrhage from vein puncture

o low platelets, prolonged clotting parameters, anemia

o citrate toxicity
 o hypocalcemia

 plasma exchange associated with greater risk of side effects than IVIG(1)

 albumin as replacement fluid during plasma exchange associated

with fewer adverse events than fresh frozen plasma (level 2 [mid-
level] evidence)

o based on subgroup analysis of randomized trial

o 109 patients with GBS having plasma exchange randomized to

albumin vs. fresh frozen plasma as replacement fluid

o 55 patients received albumin during 208 plasma exchange sessions

and 50 patients received fresh frozen plasma during 182 sessions

o comparing albumin vs. fresh frozen plasma

 no significant differences in clinical outcomes

 adverse events in 32% of sessions vs. 46% (p = 0.008)

o Reference - Crit Care Med 1993 May;21(5):651, editorial can be

found in Crit Care Med 1993 May;21(5):641

o no other trials found in Cochrane review (Cochrane Database Syst

Rev 2012 Jul 11;(7):CD001798)

Immunoabsorption

 immunoabsorption removes immunoglobulins without using human blood

product as replacement fluid and is an alternative technique to plasma
exchange(3)

 insufficient evidence to recommend use of immunoabsorption (AAN

Level U, Class IV)(3)

 sequential treatment with plasma exchange followed by

immunoabsorption is not recommended (AAN Level U, Class IV)(3)

 sequential treatment with immunoabsorption followed by IV

immunoglobulin has not been adequately tested (limited AAN Class IV)(3)

Cerebrospinal fluid filtration

 American Academy of Neurology (AAN) finds insufficient evidence to

recommend use of cerebrospinal fluid (CSF) filtration (AAN Level U,
Class II)(3)
 cerebrospinal fluid (CSF) filtration might be as effective as plasma
exchange for Guillain-Barre syndrome (GBS) (level 2 [mid-level]
evidence)
 o based on small randomized trial

o 37 patients with acute GBS randomized to CSF filtration vs. plasma

exchange

o no significant difference between treatments in symptom

improvement at 28 days (test for equivalence p = 0.0014)

o Reference - Neurology 2001 Sep 11;57(5):774

Other management

General medical measures

 blood pressure management(4)

o avoid aggressively treating blood pressure fluctuations because

patients with autonomic instability are sensitive to medications

o use of long-acting antihypertensives is contraindicated

 venous thromboembolism prophylaxis(5)

o if patient is not ambulatory, use subcutaneous heparin and

compression stockings for prophylaxis against deep vein thrombosis

o see also Deep vein thrombosis (DVT) prophylaxis for medical

patients

Rehabilitation

 inpatient multidisciplinary rehabilitation might improve functional

outcome and quality of life in patients with severe Guillain-Barre
Syndrome (GBS) (level 2 [mid-level] evidence)

o based on 2 systematic reviews (by same authors) of 3 very low

quality observational studies

o systematic review of 8 studies evaluating multidisciplinary

rehabilitation, physical therapy, or exercise for patients with GBS of
any severity

 1 randomized trial of patients with chronic phase of GBS (and

generally mild disability) described below

 3 observational studies included 128 patients with severe GBS

o 2 studies evaluated inpatient multidisciplinary rehabilitation for

up to 12 months, with ≥ 2 disciplines of therapy (including
physiotherapy, occupational therapy, social work, nursing,
psychology, other allied health providers)
 o 1 study evaluated inpatient multidisciplinary rehabilitations
(details not specified)

o all 3 studies reported improved measures of disability and

quality of life during or after rehabilitation

 4 other studies were case reports or uncontrolled series

 Reference - Eur J Phys Rehabil Med 2012 Sep;48(3):507

o Cochrane review of multidisciplinary care for adults with GBS

 no controlled trials found at time of Cochrane review

 same 3 observational studies summarized (as noted above) and

all rated as very low quality of evidence

 Reference - Cochrane Database Syst Rev 2010 Oct

6;(10):CD008505
 more intensive rehabilitation program might reduce disability
during Guillain-Barre syndrome (GBS) chronic phase (level 3
[lacking direct] evidence)

o based on randomized trial with uncertainty of importance to patients

for magnitude of effect

o 79 patients in chronic phase after GBS randomized to more vs. less

intensive rehabilitation program

 more intensive rehabilitation included outpatient center-based

rehabilitation for up to 12 weeks, with up to three 1-hour sessions
per week

 less intensive rehabilitation included home-based self-

management with 30-minute physical program (walking,
stretching) twice weekly and usual activity at home

o 69 patients included in intention-to-treat analysis at 12 months

o disability measured with functional independence measure (FIM)

score consisting of 13 items assessing activity and 4 subscales
assessing need for assistance with each item rated from 1 (total
assistance needed) to 7 (independent)

o authors reported 3-point improvement in FIM motor score to be

minimally clinically important difference

o comparing more vs. less intensive rehabilitation

 median time since GBS diagnosis 5.3 years vs. 6.5 years

 median FIM motor score at baseline 86 vs. 82 among all 79

patients
  median improvement in FIM motor score 4 vs. 0 in intention-to-
treat analysis (p = 0.003)

 improvement in FIM motor score in 68.6% vs. 32.4% (p < 0.05,

NNT 3)

 3-point improvement in FIM motor score in 54% vs. 3% (p < 0.05,

NNT 2)

 in full intention-to-treat analysis (79 patients) 3-point improvement

in FIM motor score in 47.5% vs. 15.4% (p < 0.05, NNT 4)

 deterioration in function reported in 2.9% vs. 41.2% (p < 0.001,

NNT 3)

o Reference - J Rehabil Med 2011 Jun;43(7):638 full-text

o DynaMed commentary

 proportion of patients having 3-point improvement in FIM motor

score clarified with study authors; article reported percent with
improvement followed by percent of those with improvement who
had at least 3-point improvement

 generally accepted minimally clinically important difference in FIM

motor score is 17 points (Arch Phys Med Rehabil 2006
Jan;87(1):32) but may not apply to this population

Complications and Prognosis

Complications

 respiratory failure reported in 25%-30% requiring mechanical

ventilation(1, 4)

 deep venous thrombosis and pulmonary embolism (from prolonged

immobilization)(1)

 autonomic involvement common(2, 4)

o urinary retention

o ileus

o sinus tachycardia

o hypertension

o cardiac arrhythmia

o postural hypotension

 muscle atrophy(2)
  pain(2)
 liver function disturbances associated with Guillain-Barre
syndrome

o based on cohort study

o 100 consecutive patients with Guillain-Barre syndrome (GBS) had

baseline liver functions analysis at hospital admission and repeat
testing after treatment with IV immunoglobulin (IVIG) or
plasmapheresis and then were matched with 100 patients with
subarachnoid hemorrhage

o liver function disturbances defined as plasma alanine

aminotransferase elevation (AST), gamma glutamyl transferase
elevation (GGT), or both ≥ 1.5 times upper limit of normal

o liver function disturbances observed in 38% of patients with GBS vs.

5% of patients with subarachnoid hemorrhage at admission (p <
0.0001)

o 10 of 38 patients with GBS had serologic evidence of recent

cytomegalovirus infection and 28 patients were negative for other
causes of liver damage

o in IVIG treatment group, elevated liver function studies went from

35% to 69% (NNH 3)

o Reference - Neurology 1996 Jan;46(1):96

 psychological and behavioral comorbidites associated with
Guillain-Barre syndrome

o based on systematic review of mostly observational studies

o systematic review of 18 studies (1 randomized trial and 17

observational studies) evaluating psychological and behavioral
comorbidites in 1,853 patients with inflammatory neuropathies

o 16 studies evaluated patients with Guillain-Barre syndrome

o comorbidities associated with Guillain-Barre syndrome included

anxiety (9 studies), depression (8 studies), fatigue (4 studies),
psychosis (3 studies), post traumatic stress disorder (2 studies), and
poor sleep (1 study)

o Reference - Muscle Nerve 2016 Jun;54(1):1

 asystole in case report (J Med Case Reports 2009 Jan 6;3(1):5 full-text)

Prognosis

Mortality
 4%-15% mortality reported, due to(2, 4)

o complications of critical illness such as infection, adult respiratory

distress syndrome, or pulmonary embolism (PE)

o dysautonomia (rarely)

Need for mechanical ventilation

 risk score predicts respiratory insufficiency within 1 week of

hospitalization (level 1 [likely reliable] evidence)

o based on prospective derivation and validation cohorts

o derivation cohort was 397 patients with Guillain-Barre syndrome

(GBS) from 2 randomized trials and 1 pilot study

o validation cohort was 191 patients with GBS from 1 pilot study and 1
observational study

o mechanical ventilation required within first week of hospital admission

in 22% of validation cohort and 14% of derivation cohort

o risk score (Erasmus GBS Respiratory Insufficiency Score [EGRIS],

range 0-7) derived from 3 factors assessed at hospital admission

 days between onset of weakness and hospital admission

o 0 points for > 7 days

o 1 point for 4-7 days

o 2 points for ≤ 3 days

 facial and/or bulbar weakness at hospital admission

o 0 points for absence

o 1 point for presence

 Medical Research Counsel sum score (0-5 strength ratings of 6

bilateral pairs of muscles) at hospital admission

o 0 points for score 60-51

o 1 point for score 50-41

o 2 points for score 40-31

o 3 points for score 30-21

o 4 points for score ≤ 20

o risk for respiratory insufficiency in derivation and validation cohorts

 Risk for Respiratory Insufficiency:

EGRIS Score Derivation Cohort Validatio

0-2 (low risk) 3% 4%

3-4 (intermediate risk) 25% 22%

5-7 (high risk) 63% 75%

Abbreviation: EGRIS, Erasmus Guillain-Barre Syndrome Respiratory Insufficiency S

o Reference - Ann Neurol 2010 Jun;67(6):781

 progression to mechanical ventilation in patients with GBS more
likely if rapid disease progression, bulbar dysfunction, bilateral
facial weakness, or dysautonomia

o based on retrospective chart review

o 114 patients with Guillain-Barre were admitted to intensive care unit

between January 1976 and December 1996

o 60 patients required mechanical ventilation and 54 did not

o factors associated with progression to respiratory failure included

 vital capacity < 20 mL/kg

 maximal inspiratory pressure < 30 cm H2O

 maximal expiratory pressure < 40 cm H2O

 30% reduction in vital capacity, maximal inspiratory pressure, or

maximal expiratory pressure
  serial measurements every 8 hours of pulmonary function helped
detect risk of respiratory failure

o Reference - Arch Neurol 2001 Jun;58(6):893 full-text, editorial can be

found in Arch Neurol 2001 Jun;58(6):871
 patients with GBS requiring mechanical ventilation have 20%
mortality but 79% of survivors regain independent ambulation

o based on retrospective cohort study

o 114 patients with GBS evaluated (60 required mechanical ventilation,

54 did not)

o in patients needing mechanical ventilation

 mortality 20%

 79% eventually regained independent ambulation

o compared with no ventilation, increased risk of poor recovery in

ventilated patients associated with

 increased age (p < 0.0001)

 delay > 2 days before transfer to tertiary care center (p < 0.001)

o Reference - Neurology 2000 Jun 27;54(12):2311

Neurologic outcome

 most patients with Guillain-Barre syndrome (GBS) begin to recover at 28

days(4)

o if complete recovery achieved, mean time to recovery 200 days

o minor residual signs or symptoms common (reported in 65%)

o major residual neurologic deficits reported in 10%-15%

relapse rate 5% (usually within 8 weeks)

o
 many GBS patients have residual motor and sensory loss 12
months after diagnosis

o based on cohort study

o 90 patients in randomized trial answered questionnaire regarding

their functional status at hospital discharge and at 1 year after
diagnosis of GBS

o at hospital discharge after treatment

 72% had sensory and motor disturbances in arms

 89% had sensory and motor disturbances in legs

 o 1 year after diagnosis

 33% were normal

 36% had sensory and motor disturbances in arms

 67% had sensory and motor disturbances in legs

 32% had changed work because of GBS

 30% functioned less effectively at home

 52% had altered leisure activities

o Reference - Acta Neurol Scand 2005 Jul;112(1):51

 prognosis in variant forms(4)

o most patients with acute motor axonal neuropathy (AMAN) have

more delayed recovery than classic GBS, though some cases
recover more rapidly)

o most patients with Miller Fisher syndrome recover by 6 months

 patients with Miller-Fisher syndrome may have good
prognosis for recovery with or without treatment

o based on cohort study

o 92 patients with Miller Fisher syndrome who had been treated

with IV immunoglobulin (28 patients), plasmapheresis (23
patients), or no immune treatment (41 patients) were
evaluated 1 year after onset of neurologic symptoms

o 88 patients (96%) had no residual symptoms (except for

areflexia)

o no significant differences in outcomes among groups

o Reference - Neurology 2007 Apr 3;68(14):1144

o patients with Bickerstaff brainstem encephalitis may recover by
6 months

 based on cohort study

 62 patients with Bickerstaff brainstem encephalitis (BBE) were

evaluated

 treatments included steroids, plasmapheresis, and IV

immunoglobulin alone or in combination, or no specific
immunotherapy

 37 of 56 (66%) patients with available outcome data had

complete remission by 6 months with no residual symptoms
  Reference - Brain 2003 Oct;126(Pt 10):2279 full-text
 simple clinical scoring system predicts inability to walk at 6 months
(level 1 [likely reliable] evidence)

o based on prospective derivation and validation cohorts

o derivation cohort was 388 patients with GBS in 2 randomized trials

and 1 pilot study from the Netherlands, Belgium, and Germany

o validation cohort was 274 patients with GBS in randomized trial from
centers in Europe, North America, and Australia

o patients had onset of weakness within 2 weeks of study start, and

unable to walk 10 meters unaided

o scoring system ranged from 1 to 7 points

 point for age of onset (in years)

o ≤ 40 = 0 points

o 41-60 = 0.5 points

o > 60 = 1 point

 points for diarrhea (≤ 4 weeks)

o absence = 0 points

o presence = 1 point

 points for GBS disability 2 weeks after study entry

o healthy state, or minor symptoms and capable of running = 1

point

o able to walk 10 meters or more without assistance but unable

to run = 2 points

o able to walk 10 meters across an open space with help = 3

points

o bedridden or chair-bound = 4 points

o requiring assisted ventilation for at least part of the day = 5

points

o inability to walk at 6 months increased with increasing score

 Scoring System for Prediction of Inability to Walk:

Predictive Inability to Walk at 6 Months Inability to Walk a

Scores (Derivation Cohort) (Validation C

1-3 1% 0%

3.5-4.5 6% 8%

5 25% 29%

5.5-7 51% 52%

o Reference - Erasmus GBS Outcome Score (EGOS) (Lancet Neurol

2007 Jul;6(7):589)
 modified clinical scoring system initially or at 1 week predicts
inability to walk at 4 weeks and 6 months (level 1 [likely reliable]
evidence)

o based on prospective derivation and validation cohorts

o derivation cohort was 394 patients with GBS in 2 randomized trials

and 1 pilot study from the Netherlands, Belgium, and Germany

o validation cohort was 158 patients with GBS in 1 pilot study and 1
observational study

o patients had onset of weakness within 2 weeks of study start, and

unable to walk 10 meters unaided

o Medical Research Council (MRC) sum score is sum of MRC scores

of 6 different muscles measured bilaterally, total ranges from 0
(tetraplegic) to 60 (normal)
o scoring system for modified EGOS score at presentation ranges from
0 to 9 points

 points for age at onset

o ≤ 40 years = 0 points

o 41-60 years = 1 point

o > 60 years = 2 points

 points for diarrhea (in 4 weeks preceding onset of illness)

o absence = 0 points

o presence = 1 point

 points for MRC sum score at hospital admission

o 51-60 = 0 points

o 41-50 = 2 points

o 31-40 = 4 points

o 0-30 = 6 points

o scoring system for modified EGOS score at 1 week ranges from 0 to

12 points

 points for age at onset

o ≤ 40 years = 0 points

o 41-60 years = 1 point

o > 60 years = 2 points

 points for diarrhea (in 4 weeks preceding onset of illness)

o absence = 0 points

o presence = 1 point

 points for MRC sum score at day 7 of admission

o 51-60 = 0 points

o 41-50 = 3 points

o 31-40 = 6 points

o 0-30 = 9 points
o inability to walk at 4 weeks and at 6 months increased with increasing
score (rates in derivation cohort)

Modified EGOS Score at Presentation:

Predictive Scores Inability to Walk at 4 Weeks Inability to Walk

0-2 17%-34% 3%-5%

3-4 42%-54% 8%-12%

5-6 64%-73% 18%-28%

7-9 80%-91% 38%-60%

Abbreviation: EGOS, Erasmus Guillain-Barre syndrome Outcome Score.

Modified EGOS Score at 1 Week:

Predictive Scores Inability to Walk at 4 Weeks Inability to Walk

0-1 7%-11% 0%-1%

 Modified EGOS Score at Presentation:

Predictive Scores Inability to Walk at 4 Weeks Inability to Walk

2-4 18%-38% 2%-5%

5-6 51%-64% 6%-11%

7-9 75%-90% 18%-33%

10-12 93%-98% 45%-66%

Abbreviation: EGOS, Erasmus Guillain-Barre syndrome Outcome Score.

o in independent validation cohort, modified EGOS had good

discriminative ability for predicting outcome at 4 weeks, 3 months,
and 6 months after admission

 area under curve on admission 0.75, 0.73, and 0.75 respectively

 area under curve at 1 week 0.81, 0.70, and 0.77 respectively

o Reference - Modified Erasmus GBS Outcome Score (Neurology

2011 Mar 15;76(11):968 full-text)
 1 in 4-5 children may have mild long-term muscle weakness but no
disability

o based on cohort study

o 47 children admitted to hospital with GBS and followed at least 2

years after recovery
 o muscle strength testing of 34 muscle groups revealed persisting
muscle weakness (muscle moves joint against gravity but only
minimal resistance to applied force) in at least 1 muscle group in 23%
patients

o each patient had complete functional independence

o Reference - J Pediatr 2003 Mar;142(3):305

 risk factors predicting worse outcome in patients with Guillain-
Barre include older age and prior gastroenteritis

o based on cohort study

o 297 patients aged 3-87 years with GBS were followed for up to 24
months

o 71% (212) patients recovered, 16% (48) had residual symptoms, and
11% (33) died

o mean time to nadir was 12 days, improvement 28 days and clinical

recovery 200 days

o factors associated with increased recovery time

 age > 54 years

 antecedent gastroenteritis

 respiratory insufficiency at nadir

 latency to nadir > 4 weeks

 duration of active disease > 4 weeks

 electrophysiological signs of axonopathy

oReference - Brain 1996 Dec;119 (Pt 6):2053, commentary can be

found in Brain 1998 Apr;121 (Pt 4):767 PDF
 serologic confirmation of Campylobacter jejuni infection associated
with worse outcomes in patients with Guillain-Barre syndrome

o based on cohort study

o 383 patients with GBS were randomized to plasma exchange vs.

immunoglobulin and followed for 48 weeks

o 229 patients had pretreatment serum compared to serum obtained

14 days after randomization (posttreatment)

o serologic evidence of infection found for

 C. jejuni in 23% (53 patients)

 cytomegalovirus in 8% (19 patients)

  Epstein-Barr virus in 2% (4 patients)

o C. jejuni infection associated with

 neurophysiologic criteria for axonal neuropathy

 antiganglioside GM1 antibodies

 pure motor GBS

 lower levels of cerebrospinal fluid protein

 worse neurologic outcome

inexcitable nerves on early nerve conduction studies associated with

worse outcomes at 48 weeks

o based on cohort study

o 369 patients with GBS in randomized trial had electrophysiological testing

within 15 days of symptom onset and were classified by motor nerve
conduction

o neurophysiological classification based on nerve conduction studies

included

 primary demyelinating in 69% (252)

 primary axonal in 3% (10)

 inexcitable in 3% (12)

 normal in 2% (9)

 equivocal (not meeting criteria for other groups) in 23% (84)

o patients not walking or dead at 48 weeks

 17% (44) of demyelinating group

 10% (1) of axonal group

 50% (6) of inexcitable group

 11% (1) of normal group

 7% (6) of equivocal group