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Guillain-Barre SyndromePeter D. Donofrio, MD, FAAN

ABSTRACTPurpose of Review: This article reviews the current state of Guillain-Barre syndrome(GBS), including its clinical presentation, evaluation, pathophysiology, and treatment.Recent Findings: GBS is an acute/subacute-onset polyradiculoneuropathy typicallypresenting with sensory symptoms and weakness over several days, often leading toquadriparesis. Approximately 70% of patients report a recent preceding upper orlower respiratory tract infection or gastrointestinal illness. Approximately 30% ofpatients require intubation and ventilation because of respiratory failure. Nerveconduction studies in the acute inflammatory demyelinating polyradiculoneuropathy(AIDP) form of GBS typically show evidence for a multifocal demyelinating process,including conduction block or temporal dispersion in motor nerves. Sural sparing is acommon phenomenon when testing sensory nerves. CSF analysis commonly showsan elevated protein, but this elevation may not be present until the third week of theillness. Patients with AIDP are treated with best medical management and either IVimmunoglobulin (IVIg) or plasma exchange.Summary: GBS is a common form of acute quadriparesis; a high level of suspicion isneeded for early diagnosis. With appropriate therapy, most patients make a very goodto complete recovery.

Continuum (Minneap Minn) 2017;23(5):1295–1309.

INTRODUCTIONThe clinical presentation of Guillain-Barre syndrome (GBS) was first de-scribed by Landry in 1859. He reportedfive patients with an ascending post-infectious polyneuropathy and all thefeatures of GBS except for areflexia.The illness has been recognized asGBS since 1916, when Guillain, Barre,and Strohl described two French sol-diers who contracted the illness dur-ing World War I. They described theclinical features we now recognize,including elevation of CSF protein.For unclear reasons, Strohl’s namewas dropped from the term GBSbeginning in the early 20th century.

Since the eradication of polio, GBShas become the most frequent causeof acute or subacute flaccid weaknessworldwide.1,2 GBS typically occurs inpatients who were previously healthyand not burdened by prior autoim-

mune or systemic illnesses. The inci-dence of GBS is 0.5 per 100,000 to2 per 100,000, and it affects menslightly more than women.1,2 It occursduring all seasons. The risk of devel-oping GBS over the lifetime of anindividual has been estimated to beless than 1 in 1000.1

GBS is an acute- or subacute-onsetpolyradiculoneuropathy that often fol-lows an upper or lower respiratoryillness or gastroenteritis by 10 to 14 days.Approximately 70% of patients canidentify a preceding illness, althoughit is often benign and may be mini-mized or forgotten by the patient.1Y3

Many infections have been associatedwith GBS, including Cytomegalovirus,Mycoplasma pneumoniae, Epstein-Barr virus, influenza A, Haemophilusinfluenzae, Enterovirus, and Campylo-bacter jejuni.4,5 In approximately 40%of patients, antibodies will be found

Address correspondence toDr Peter D. Donofrio, A-0118MCN AA0204E, Nashville,TN 37232,[email protected].

Relationship Disclosure:Dr Donofrio has served on theeditorial board of Muscle &Nerve and receives publishingroyalties from Demos MedicalPublishing. Dr Donofrioserves as a consultant for andhas received personalcompensation for speakingengagements from CSLBehring and Grifols.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:Dr Donofrio reports nodisclosure.

* 2017 American Academyof Neurology.

1295Continuum (Minneap Minn) 2017;23(5):1295–1309 ContinuumJournal.com

Review Article

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

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against the Campylobacter antigen,thus making it the most commonlyidentified organism associated withGBS.1Y3 GBS appears to be morecommon after infection with the Zikavirus, and the onset of weaknessfollows within a few days after infec-tion.6 Other authors have challengedthis relationship, citing the inability tosatisfy strict criteria for GBS.7 Otherless common precipitants are surgery,pregnancy, cancer, and vaccinations.

During the 1976 flu vaccinationperiod with the influenza A/H1N1antigen, the incidence of GBS rose9.5-fold.8 Epidemiologic studies ofGBS after flu vaccinations in subse-quent years have found very small orno increase in GBS. Some studieshave shown a protective effect fromthe flu vaccination in preventing GBS.9

When one considers the effectivenessof the flu vaccination in preventingdisease (60% in most years) and thehigh incidence of the natural influenzainfection (5%) for a worldwide popu-lation, the importance of the fluvaccination for public health reasonscannot be overstated.9

DIAGNOSISGBS evolves over days, often begin-ning with numbness in the lowerlimbs and weakness in the samedistribution. The progression of symp-toms, particularly weakness, can berapid, resulting in quadriplegia withina few days. Approximately 50% ofpatients achieve maximum weaknessby 2 weeks, 80% by 3 weeks, and90% by 4 weeks.10 Progression beyond4 weeks is unusual and should raiseconcern for other illnesses, particularlychronic inflammatory demyelinatingpolyradiculoneuropathy (CIDP). Neu-ropathic pain is observed in up to 66%of patients and is often localized to thelower back and thighs.11 Determiningthe cause of the pain can be challenging

before the diagnosis of GBS is estab-lished. Since GBS is a polyradiculo-neuropathy, weakness may be moreproximal than distal, but in mostpatients, the weakness begins distallyand spreads proximally. In rare cases,the weakness may be localized to thelegs only (giving the appearance ofparaplegia), but absent or reducedreflexes or electrodiagnostic findingsin the arms betray upper limb involve-ment. The sensory examination may benormal or show minor deficiencies invibration and proprioception, abnor-malities expected in patients with largemyelinated fiber involvement. Essen-tially all patients have areflexia or atleast hyporeflexia at some time in theillness (Case 4-1). Approximately 50%of patients develop some degree offacial weakness, and other cranialnerves may be affected during theheight of illness.3,10,12 Weakness attrib-uted to cranial nerves includes oculardysmotility, pupillary changes, andptosis. Ophthalmoparesis has beenreported in approximately 20% ofpatients with GBS.3,10,12 Thirty percentof patients with GBS develop respira-tory failure from phrenic nerve disease,requiring intubation and ventilation.1Y3

Many progress to tracheostomy untilthe acute phase of the illness resolves.Autonomic involvement is common inGBS, with the most common manifes-tations being tachycardia, bradycardia,hypertension and hypotension, gastrichypomotility, and urinary retention.1Y3

Autonomic involvement may be thecause of death in some patients withGBS. Table 4-2 lists diagnostic criteriafor GBS.

Brighton CollaborationIn 2009 and 2011, the Brighton Col-laboration published case definitionsand guidelines for the collection,analysis, and presentation of immuni-zation safety data for making the

KEY POINTS

h Guillain-Barre syndromeis the most frequentcause of acute orsubacute flaccidweakness worldwide.

h Campylobacter jejuni isthe most commonlyidentified organismassociated withGuillain-Barresyndrome.

h Approximately 50%of patients withGuillain-Barre syndromeachieve maximumweakness by 2 weeks,80% by 3 weeks, and90% by 4 weeks.

h Thirty percent ofpatients withGuillain-Barre syndromedevelop respiratoryfailure from phrenicnerve disease,requiring intubationand ventilation.

1296 ContinuumJournal.com October 2017

Guillain-Barre Syndrome



Case 4-1A 35-year-old man experienced 3 days of progressive numbness and weakness after exposure to hisdaughter’s viral illness. Neurologic examination was notable for weakness of eye closure on bothsides. He was weak proximally and distally in the upper extremities and proximally more than distallyin the lower extremities. He had diffuse areflexia; plantar responses were mute. Sensation wasdecreased in the arms to the mid clavicle and in the legs to the groin.

Nerve conduction studies showed findings consistent with a multifocal demyelinatingpolyneuropathy (Table 4-1). The sural response was normal; the ulnar sensory response was absent.The fibular (peroneal) and tibial motor distal latencies were prolonged. Conduction slowing wasrecorded in all but one motor nerve. All F-wave latencies were markedly prolonged. Conduction blockwas recorded along all motor nerves (Figure 4-1).

The patient was diagnosed as having acute inflammatory demyelinating polyradiculoneuropathy(AIDP) and treated with a 5-day course of IV immunoglobulin (IVIg). Lumbar puncture was normalexcept for a CSF protein of 80 mg/dL. His condition was complicated by burning pain in the hips andthighs, for which he was treated with gabapentin and opioids. He was transferred to rehabilitationafter 9 days in the hospital.

When evaluated 2 months after hospitalization, the patient had regained most of his strength. Headmitted to occasional tingling in the feet. He was able to return to his work as an airplane mechanic.

TABLE 4-1 Nerve Conduction Study Results for the Patient in Case 4-1

Nerve and SiteLatency(Milliseconds)

Amplitude(Millivolts)

Conduction Velocity(Meters per Second)

Right median motor wrist 4.4 2.8 mV

Right median motor elbow 10.3 1.7 mVa 41

Right ulnar motor wrist 3.2 9.8 mV

Right ulnar motor below elbow 6.7 7.9 mV 59

Right ulnar motor above elbow 8.6 7.1 mV 47

Right tibial motor ankle 8.1 3.2 mV

Right tibial motor popliteal fossa 18.1 1.4 mVa 39

Right fibular (peroneal) motor ankle 10.0 2.3 mV

Right fibular (peroneal) motorbelow knee

20.7 0.9 mVa 29

Right fibular (peroneal) motorabove knee

23.0 0.8 mV 38

Left fibular (peroneal) motor ankle 7.1 2.8 mVa

Left fibular (peroneal) motorbelow knee

16.3 1.3 mV 33

Left fibular (peroneal) motorabove knee

18.4 1.2 mV 43

Left tibial motor ankle 7.0 6.6 mV

Left tibial motor popliteal fossa 17.4 1.8 mVa 37

Right ulnar sensory No response No response

Right sural sensory 3.1 29 2Va Conduction block observed.

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diagnosis of GBS.13 For GBS andMiller Fisher syndrome (also referredto by some neurologists as Fisher syn-drome), the collaboration developedthree levels of diagnostic certainty use-ful to determine the likelihood of thediagnosis. Achieving level 1 is the stron-gest argument for the diagnosis of GBSand level 3 the weakest (Table 4-3).Clinical case definitions have also beencreated for three levels of certainty for

Miller Fisher syndrome. Although notdeveloped to assess the certainty ofGBS in patients who have not receiveda recent vaccination, the criteria createa yardstick for determining the likeli-hood of GBS. Not all patients initiallythought to have GBS have the diagno-sis confirmed. Asbury and Cornblath10

have published features that raisedoubt or eliminate the diagnosis ofGBS (Table 4-4).

Neurologic examination revealed normal strength in the upper extremities and mild weakness of hipflexion and ankle flexion and extension. Muscle stretch reflexes were absent. Sensation was normal topinprick and light touch. Routine gait was normal.

When assessed 5 months later, he had made a complete recovery except for mild leg weakness andtingling in the feet. On examination, facial strength was normal. Strength was normal in the upperextremities and mildly reduced at the hips and ankles. Reflexes were 1+ in the upper extremities, 2+ atthe knees, and 1+ at the ankles. Tandem gait was performed without difficulty.

Comment. The patient achieved an excellent recovery 7 months after the onset of AIDP. Atonset, he showed both proximal and distal weakness in the lower extremities, a clinical featureof a polyradiculoneuropathy. He regained almost all his strength, sensation, reflexes, and gait. Hecontinued to have reduced reflexes at the ankles. Over time, he is likely to make a complete recovery.

FIGURE 4-1 Fibular (peroneal) motor nerve conduction study of the patient in Case 4-1 recorded from the extensordigitorum brevis (EDB) muscle showing a markedly prolonged distal latency, conduction block below andabove the knee, and slowing of conduction velocity.

Continued from page 1297





Variants of Guillain-BarreSyndromeSince the initial reports of GBS, vari-ants have been identified that differfrom the AIDP presentation of GBSthat is the most common form of theillness. Variants of GBS include acutemotor axonal neuropathy (AMAN),acute motor-sensory axonal neuropa-thy (AMSAN), Miller Fisher syndrome,a paraplegic form of GBS, and thepharyngeal-cervical-brachial presenta-tion. Rare and poorly defined formsof GBS are acute autonomic neuropa-

thy and acute sensory neuropathiesthat follow viral illnesses.

AMAN is more common in childrenduring the summer and much morecommon in northern China thanthe United States, Europe, and otherareas of Asia.14 The illness is purelymotor without sensory symptoms andsigns. Nerve conduction studies showreduced compound muscle actionpotential (CMAP) amplitudes, normallatencies and conduction velocities,and normal sensory studies. AMSANis similar to AMAN except for theaddition of sensory involvement.15

It differs greatly from AMAN in thelater age of onset, involvement ofsensory fibers clinically and on nerveconduction studies, broader geographicdistribution, a more protracted course,and slower and incomplete improve-ment (Case 4-2).15

Miller Fisher syndrome is classifiedas an acute or subacute demyelinatingpolyradiculoneuropathy, but its clinicalpresentation differs markedly from typ-ical GBS.1Y3 Patients with Miller Fishersyndrome present with the triad ofophthalmoparesis or ophthalmoplegia,areflexia, and ataxia. Some patientshave lower brainstem involvement,such as facial and pharyngeal weak-ness. The illness is often grouped withBickerstaff brainstem encephalitis,which has a similar presentation plususually an encephalopathy and corti-cospinal tract dysfunction.16 Patientswith Bickerstaff brainstem encephalitiscommonly have abnormal imagingstudies of the brainstem, as expectedin a brainstem encephalitis.16 Patientswith either condition often have anti-GQ1b antibodies found in their serum.The prognosis in both Miller Fishersyndrome and Bickerstaff brainstemencephalitis is favorable. Most patientsimprove within 1 to 2 months andmake a complete recovery in 6 monthswithout specific treatment.

KEY POINT

h Patients with MillerFisher syndrome presentwith the triad ofophthalmoparesis orophthalmoplegia,areflexia, and ataxia.

TABLE 4-2 Diagnostic Criteriafor Guillain-BarreSyndromea

b Progressive weakness in thelegs and armsb

b Areflexia or hyporeflexiab

b Progression of symptomslasting up to 4 weeks

b Relative symmetry ofweakness and sensory loss

b Sensory symptoms andsigns, if present, lessimpressive then weakness

b Pain is common, often in theback and legs

b Autonomic dysfunctioncommon

b Absence of fever

b Albuminocytologicdissociation in theCSF by 3 weeks

b Postgadoliniumenhancement of peripheralnerve roots and caudaequina

a Data from Willison HJ, et al,Lancet,1 thelancet.com/journals/lancet/article/PIIS0140-6736(16)00339-1/fulltext; Esposito S, Longo MR,Autoimmun Rev,2 sciencedirect.com/science/article/pii/S1568997216302178;and Asbury AK, Cornblath DR, AnnNeurol,10 onlinelibrary.wiley.com/doi/10.1002/ana.410270707/abstract.

b Required for the diagnosis.



http://thelancet.com/journals/lancet/article/PIIS0140-6736(16)00339-1/fulltext



http://sciencedirect.com/science/article/pii/S1568997216302178


http://onlinelibrary.wiley.com/doi/10.1002/ana.410270707/abstract



TABLE 4-3 Brighton Collaboration Diagnostic Criteria forGuillain-Barre Syndromea

b Level 1 of Diagnostic Certainty

Bilateral AND flaccid weakness of the limbs

AND

Decreased or absent deep tendon reflexes in weak limbs

AND

Monophasic illness pattern AND interval between onset and nadir ofweakness between 12 hours and 28 days AND subsequent clinical plateau

ANDElectrophysiologic findings consistent with Guillain-Barre syndrome (GBS)

AND

Albuminocytologic dissociation (ie, elevation of CSF protein level abovelaboratory normal value and CSF total white blood cell count less than50 cells/2L)

AND

Absence of an identified alternative diagnosis for weakness



AND


AND

Monophasic illness pattern AND interval between onset and nadir ofweakness between 12 hours and 28 days AND subsequent clinicalplateau

AND

CSF total white blood cell count less than 50 cells/2L (with or withoutCSF protein elevation above laboratory normal value)

OR

If CSF not collected or results not available, electrophysiologic studiesconsistent with GBS

AND

Absence of identified alternative diagnosis for weakness



AND


AND

Monophasic illness pattern AND interval between onset and nadir ofweakness between 12 hours and 28 days AND subsequent clinical plateau

AND

Absence of identified alternative diagnosis for weakness

CSF = cerebrospinal fluid.a Modified with permission from Sejvar JJ, et al, Vaccine.13 B 2010 Elsevier.sciencedirect.com/science/article/pii/S0264410X1000798X.




http://sciencedirect.com/science/article/pii/S0264410X1000798X


TABLE 4-4 Features Casting Doubt or Eliminating a Diagnosis ofGuillain-Barre Syndromea

b Features That Cast Doubt on a Diagnosis of Guillain-Barre Syndrome

Marked persistent asymmetry of weakness

Bowel or bladder dysfunction at onset

Presence of greater than 50 polymorphonuclear leukocytes in CSF

Sharp sensory level

Severe pulmonary dysfunction with little or no limb weakness at onset

Fever at onset

Slow progression of weakness more than 4 weeks

b Features That Eliminate the Diagnosis of Guillain-Barre Syndrome

Current history of hexacarbon abuse

Abnormal porphyrin metabolism, particularly acute intermittent porphyria

Recent diphtheric infection

Exposure to lead

A purely sensory presentation

CSF = cerebrospinal fluid.a Data from Esposito S, Longo MR, Autoimmun Rev,2 sciencedirect.com/science/article/pii/S1568997216302178, and Asbury AK, Cornblath DR, Ann Neurol,10

onlinelibrary.wiley.com/doi/10.1002/ana.410270707/abstract.

Case 4-2A 44-year-old man was in good health until he developed an eye infection.Several days later, he experienced numbness in the lower extremities thatquickly progressed to the upper extremities. This was followed by weaknessand eventually quadriparesis. Lumbar puncture revealed an elevated protein.Nerve conduction studies showed evidence for a severe motor greater thansensory axon loss neuropathy. He was diagnosed as having the acutemotor-sensory axonal neuropathy (AMSAN) form of Guillain-Barre syndrome(GBS). Over several days, he developed respiratory failure requiring intubation,subsequent tracheostomy, and feeding tube placement for nutrition.Hospitalizationwas complicated by pneumonia and bilateral lower extremitydeep venous thromboses. He was treated with plasma exchange. He waseventually extubated and transferred to rehabilitation.

When assessed 4 months after the onset of the illness, his primarysymptom was severe neuropathic pain in the feet. Examination showedbifacial weakness, mild weakness proximally in the arms and legs, andlittle movement of the toes and ankles. He was areflexic. Light touch wasdiminished from the toes to the mid shins. He could not tolerate stroking thebottom of his foot or the application of the tuning fork to his toes. He couldwalk with a walker. When reevaluated 7 months later, the pain in his feetwas improved on a regimen of methadone, pregabalin, and "-lipoic acid.There was no improvement in facial motor function. He showed improvedstrength at the ankles bilaterally. He was able to return to work as anelectrician wearing ankle-foot orthoses and boots to stabilize his ankles.

Continued on page 1302







Laboratory TestingAt present, no biomarkers exist in theblood, urine, or CSF that confirm thediagnosis of GBS. Most patients withGBS will have an elevated CSF protein,but this laboratory finding may not bepresent until 3 weeks after the onsetof the illness. A pleocytosis (greaterthan 5 white blood cells) is usually notpresent in patients with GBS, butapproximately 15% of patients have aCSF white blood cell count of 10 to50 cells per high-power field.2

If a pleocytosis is present, it raisessuspicion for an infectious processsuch as human immunodeficiencyvirus (HIV), cytomegalovirus, or Lymedisease; sarcoidosis; or carcinoma-tous or lymphomatous meningitis.For this reason, any patient withpresumed GBS and an elevatedCSF white blood cell count must beassessed for an infectious or neo-plastic etiology. It has become com-monplace for neurologists to omitperforming a CSF analysis when theclinical presentation and electrophysi-ology strongly support the diagnosis ofGBS. Although an increasingly acceptedpractice, it lessens the certainty of thediagnosis and opens the possibilityof misdiagnosis.

ElectrodiagnosisNerve conduction studies and EMGare performed in patients with GBS tosupport the diagnosis and to eliminatemimicking illnesses. Nerve conductionstudies are not required to diagnose

GBS but are necessary to differentiateAIDP from AMAN and AMSAN andconsequently provide data for prog-nostic determination.1Y3 In the firstfew days of the illness, nerve conduc-tion studies may be normal or onlyshow subtle changes of demyelin-ation, such as prolonged or absent Fwaves and H reflexes, and patchychanges in distal latencies in patientswith AIDP.17,18 As the disease evolves,the classic features of a multifocaldemyelinating polyradiculoneuropathyevolve, showing conduction block,temporal dispersion, and prolongeddistal and F-wave latencies.17 Nerveconduction slowing, a feature manyphysicians associate with GBS, maynot be recorded until several weeksinto the illness.17 Sensory nerve con-duction studies may show a character-istic sural nerve sparing, a term usedto describe the presence of normalsural responses in the setting of abnor-mal upper limb sensory results.17,18

When noted, this finding lends strongconsideration for the diagnosis of GBSin the proper clinical setting, as suralsparing is not commonly observed inlength-dependent neuropathies. Thedegree of prolongation of distal laten-cies and F waves, the severity of slowingof conduction velocity, and the amountof conduction block and temporaldispersion necessary to verify a demye-linating neuropathy differ among labo-ratories and electromyographers. Theneedle examination in GBS is oftendeferred until the fourth week of the

KEY POINTS

h No biomarkers existin the blood, urine, orCSF that confirmthe diagnosis ofGuillain-Barresyndrome.

h In the first few daysafter onset ofGuillain-Barresyndrome, nerveconduction studies maybe normal or only showsubtle changes ofdemyelination, such asprolonged or absentF waves and H reflexesand patchy changes indistal latencies.

Comment. This case demonstrates the AMSAN form of GBS. Patients areoften left with severe deficits, particularly in distal strength, but thispatient also showed bifacial weakness. IV immunoglobulin (IVIg) was notprescribed because of deep vein thromboses, a relative contraindicationfor its use. The patient also demonstrated the persistence of neuropathicpain in GBS, often requiring several agents for management. The presenceof severe weakness approximately 1 year after the onset of illness portendsthe likelihood of significant permanent ankle and bifacial weakness.

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illness or later, when the likelihood offinding active denervation is the stron-gest. In this setting, one would findpositive sharp waves, fibrillation poten-tials, and reduced recruitment of motorunits of normal amplitude and duration.Abnormalities might be found in prox-imal and distal muscles and in theparaspinal muscles since GBS is amultifocal polyradiculoneuropathy. Fea-tures of chronic denervation andreinnervation will be recorded monthsafter the onset of the illness in clinicallyweak muscles. The results of nerveconduction studies can be used topredict prognosis. Markedly reducedCMAP amplitudes are associated with aprotracted hospitalization and recovery.

A confounding problem when per-forming serial nerve conduction studiesin patients with GBS is the difficulty indetermining a pattern of improvementor worsening from one study to thenext.1,18 The electrophysiologic charac-teristics and pattern can change in anindividual. What appears to be AIDP inthe initial study may evolve into apattern more consistent with AMAN asconduction block and temporal dis-persion are reversed by myelin repairand secondary axonal loss becomesthe predominant pathology. Com-pounding the problem is the difficultyof performing nerve conduction studiesin patients who are critically ill inthe intensive care unit (ICU) setting,where warm temperatures can be chal-lenging to maintain and electrical andmechanical interference may precludea thorough and interpretable study.Comparing a follow-up study per-formed in the comfortable setting ofa warm EMG laboratory to the resultsfrom a prior study recorded in a coldICU can be frustrating.

Imaging StudiesIn recent years, MRI scanning of thebrain and spine has been commonly

performed to assess for gadoliniumenhancement of nerve roots and toeliminate other causes of quadriparesis,particularly transverse myelitis, sub-acute compressive myelopathy, andinfiltrating illnesses of the roots andthe spinal cord. As many as 95% ofchildren with GBS show enhancementof the lumbar roots secondary to theinflammatory process; this finding addsconfidence to the diagnosis of GBS.19,20

DISORDERS MIMICKINGGUILLAIN-BARRE SYNDROMEMany disorders may appear to re-semble GBS in the first few days ofpresentation and should be consid-ered in the differential diagnosis ofGBS (Table 4-5).10,21,22 The most com-mon of the group are critical illnessneuropathy and myopathy, tick paraly-sis, acute intermittent porphyria, andHIV infection. Consideration for GBSoften arises in patients who have beencritically ill with sepsis for several daysto weeks, are quadriparetic, and aredifficult to wean from the ventilator.23

The presence of fever and multiorganfailure favors critical illness neuropathy.Most of these patients eventually arediagnosed with critical illness neuropa-thy or myopathy.23

Tick paralysis is seen in childrenduring tick season.24 Differentiating itfrom GBS are the presence of diplo-pia, pupillary changes (dilated pupils),the lack of sensory symptoms andsensory examination findings, andnormal CSF results.24 On nerve con-duction studies, children with tickparalysis have low CMAP potentialsand normal sensory results. The tickis commonly located on the nape ofthe neck or scalp. Its removal resultsin rapid improvement of weakness.

Acute intermittent porphyria mayclosely resemble GBS, particularly ifautonomic dysfunction is present.25

Differentiating points are the presence

KEY POINT

h Markedly reducedcompound muscleaction potentialamplitudes are associatedwith a protractedhospitalization andrecovery.




of psychiatric disease, prior attacks,and a potential precipitating medica-tion in acute intermittent porphyria.

GBS is more common in patientswith HIV and may occur before or at

the time of seroconversion.26 Nerveconduction studies are identical tothose in nonYHIV-associated GBS. Ahelpful differentiating point is thepresence of a pleocytosis on CSFanalysis in patients with HIV.1Y3,26

Acute arsenic poisoning may re-semble GBS except for the multiorganinvolvement that typically is associatedwith arsenic intoxication.27 The pre-ceding nausea and vomiting of acutearsenic poisoning may be misinter-preted as a gastroenteritis precedingGBS and may strengthen the impres-sion that the patient has GBS.

Poliomyelitis is usually seen in thesetting of prior meningitis, and theweakness is usually asymmetric andassociated with pain. The patient withpolio should not have sensory symp-toms or signs. In most patients, itshould not be difficult to exclude myas-thenia gravis, an acute presentation ofamyotrophic lateral sclerosis, or a cervi-cal form of transverse myelitis fromGBS. Patients with West Nile encepha-lomyelitis typically have a fever, rash,asymmetric weakness, back pain, nor-mal sensation, and a CSF pleocytosis.28

Botulism begins after exposure totainted food or in patients withinfected wounds.29 Profound auto-nomic dysfunction in patients whoare quadriplegic is often the key todiagnosis (dilated pupils, blurring ofvision, urinary retention, constipa-tion). Patients with botulism oftenhave ptosis, dilated and unresponsivepupils, and paralyzed extraocularmovements, findings rare in GBS.29

IMMUNOPATHOGENESISUntil the clinical presentations of AMANand AMSAN were reported, GBS wasconsidered a multifocal demyelinatingpolyneuropathy that led to secondaryaxonal loss. Recent data suggest thatGuillain-Barre syndrome is primarily anantibody-mediated disorder rather than

KEY POINTS

h Guillain-Barre syndromeis more common inpatients with humanimmunodeficiency virusand may occur beforeor at the time ofseroconversion.

h Patients with botulismoften have ptosis,dilated andunresponsive pupils,and paralyzedextraocular movements,findings rare inGuillain-Barresyndrome.

TABLE 4-5 DisordersThatMimicGuillain-BarreSyndromea

b Critical illness neuropathyand myopathy

b Neurotoxin poisoning: tickparalysis, snake bite, marinetoxins, buckthorn, pyrinuron,organophosphates, n-hexane

b Acute intermittent porphyria,hepatic porphyrias

b Heavy metal poisoning,particularly arsenic

b Infectious: poliomyelitis,West Nile encephalomyelitis,human immunodeficiencyvirus (HIV), cytomegalovirus,Lyme disease, diphtheria,botulism

b Myasthenia gravis

b Amyotrophic lateral sclerosis

b Transverse myelitis

b Wernicke encephalopathy

b Vitamin B12 deficiency(severe)

b Acute/subacute compressivemyelopathy

b Metabolic abnormalities:hypermagnesemia,hypophosphatemia

b Drug adverse effect:amiodarone, cytarabine,streptokinase, suramin

b Vasculitis

a Data from Asbury AK, CornblathDR, Ann Neurol,10 onlinelibrary.wiley.com/doi/10.1002/ana.410270707/abstract; Sciacca G,et al, Neurol Sci,21 link.springer.com/article/10.1007/s10072-015-2450-4?no-access=true; and Levin KH,Neurologist,22 journals.lww.com/theneurologist/Abstract/2004/03000/Variants_and_Mimics_of_Guillain_Barre_Syndrome.1.aspx.







http://link.springer.com/article/10.1007/s10072-015-2450-4?no-access=true



http://journals.lww.com/theneurologist/Abstract/2004/03000/Variants_and_Mimics_of_Guillain_Barre_Syndrome.1.aspx



journals.lww.com/theneurologist/Abstract/2004/03000/Variants_and_Mimics_of_Guillain_Barre_Syndrome.1.aspx


a T-cellYmediated disorder.1Y3,30 Withthe description of AMAN came therealization that the axons could be theprimary focus of injury by the autoim-mune process. Antibody biomarkershave been identified against neuronalmembrane gangliosides GM1 andGD1a in patients with AMAN.2 Theantibodies arise as a result of molecularmimicry between the lipooligosac-charides of infective organisms andthe surface molecules on the motoraxons. IgG1 and IgG3 subclass immu-noglobulins are thought to bind withGM1 and GD1a gangliosides and toinduce axon injury by complementfixation, attracting macrophages anddepositing membrane attack com-plexes on the axolemma.2 Rapid repairof nodal and paranodal conductionblock has been used to explain thequick recovery of children with AMAN.

Despite our understanding of thepathology and electrodiagnosis ofAIDP and its much greater prevalencethan AMAN and AMSAN, the immuno-logic sequence causing AIDP is lessunderstood. Since a wide range ofviruses and bacterial agents can incitean antibody in AIDP, it has been difficultto find a common antigenic stimulusfor the illness. Equally difficult has beenthe identification of specific antibodybiomarkers in myelin.

MANAGEMENTComprehensive treatment of GBSrequires close attention to generalmedical care and immunologic treat-ment.1,2 Early in the illness, patientsmust be monitored carefully for respi-ratory failure, cardiac arrhythmias,dysphagia, ileus, and potential hypo-tension and hypertension. Frequentmeasurements of respiratory reserve,such as forced vital capacity andmaximal expiratory pressure, shouldbe ordered, particularly for patientswho are markedly weak. It is often

advisable to admit the patient to theICU prematurely if one suspects ahigh probability for respiratory failure.This is especially true when the patientis admitted to a regular hospitalfloor where nursing care may be lessavailable, particularly at night. Prophy-laxis for deep vein thrombosis anddecubitus ulcers is important. Surveil-lance for pulmonary and urinarybladder infections prevents furthercomplications. Autonomic dysfunctionmay cause bladder retention and con-stipation. Early physical therapy andoccupational therapy are advisable tomaintain range of motion, preventcontractures, and begin the rehabilita-tion process. Pain should be managedusing pharmacologic agents thatare effective for neuropathic pain.11

Popular agents are gabapentin, pre-gabalin, and low doses of tricyclicantidepressants. Opioids can be usedfor short-term treatment of pain butshould be avoided for long-termpain management.

Evidence-based research supportsthe use of immunotherapy for GBS;proven therapies are IV immunoglob-ulin (IVIg) and plasma exchange,which have been shown to be equallyefficacious in the management ofGBS.31Y35 One or the other should bestarted as soon as possible once thediagnosis of GBS has been consid-ered. A common dosing schedule forIVIg is 0.4 g/kg/d for 5 days. It is notknown whether this treatment sched-ule is superior to administering thesame total dose over 2 or 3 days.As early as the mid-1980s, plasmaexchange was shown to be superior tobest medical management of GBS.31

For safety reasons, to prevent majorshifts in fluid balance, it is advisable toperform plasma exchange every otherday. Over time, IVIg has become thepreferred treatment for GBS becauseof its widespread availability, fewer

KEY POINTS

h Early in the illness,patients withGuillain-Barre syndromemust be monitoredcarefully for respiratoryfailure, cardiacarrhythmias, dysphagia,and potentialhypotension andhypertension.

h It is often advisable toadmit patients withGuillain-Barre syndrometo the intensive careunit prematurely if onesuspects a highprobability for respiratoryfailure.

h Intravenousimmunoglobulin andplasma exchange havebeen shown to beequally efficacious asimmunotherapy forthe treatment ofGuillain-Barresyndrome.




associated complications, peripheralvein access, and convenience of infus-ing at night and on weekends. In mostmedical centers, the cost of IVIg andplasma exchange is comparable. Nopublished evidence suggests that asecond course of IVIg is superior to asingle course. In one large study,plasma exchange followed by IVIg wasnot shown to be superior to eithertreatment alone.35

Oral and IV corticosteroids havenot shown efficacy in the treatmentof GBS used alone or in combinationwith IVIg or plasma exchange.36 Weakevidence exists that patients with GBStreated with steroids fared worse thanthose receiving best medical manage-ment.36 Table 4-6 summarizes the man-agement approach for GBS, includingbest medical care and immunotherapy.

Treatment-related FluctuationsTreatment-related fluctuations are de-fined as worsening of weakness afteran initial improvement or after stabili-zation following treatment with IVIg orplasma exchange.37 Treatment-relatedfluctuations occur in approximately10% of patients withGBS.37 They usuallytake place within the first 2 monthsafter treatment is initiated and arethought to relate to continuation of anactive immune attack on the peripheralnervous system.37 Treatment-relatedfluctuations are usually treated with an-other course of IVIg or plasma exchange,and the treatment is often beneficial.

Approximately 5% to 16% of pa-tients with CIDP present acutely,37

and the worsening after initial treat-ment and improvement is considereda treatment-related fluctuation. Theinitial phase of the illness is almostalways diagnosed as GBS. Over time,the question of CIDP arises if thepatient has a long protracted courseof weakness, particularly if progres-sion occurs after the first 4 weeks. If

the patient experiences more thanone treatment-related fluctuation, andparticularly if it occurs 2 months ormore after the onset of the illness,then the diagnosis of CIDP becomes astrong consideration.37

PROGNOSISThe prognosis for most patients withGBS is for good to excellent recovery.Approximately 87% experience fullrecovery or minor deficits.38 Somepatients do not regain full strength inthe hands or movement of the ankles.Residual bilateral footdrop is a notuncommon sequela of GBS requiringankle-foot orthoses and light boots topromote ambulation. Numbness and

KEY POINT

h Over time, IVimmunoglobulin hasbecome the preferredtreatment forGuillain-Barresyndrome because of itswidespread availability,fewer associatedcomplications, peripheralvein access, andconvenience ofinfusing at night andon weekends.

TABLE 4-6 Management ofGuillain-BarreSyndromea

b Frequent monitoring ofrespiratory function

b Monitoring for autonomicdysfunction

b Deep venous thrombosisprophylaxis

b Treatment ofconstipation/ileus

b Nonopioid managementof neuropathic pain

b Psychosocial support

b Physical, occupational,and speech therapy

b Immunologic treatmentwith IV immunoglobulin(IVIg) or plasma exchange

b Corticosteroid treatmentnot indicated

a Data from Willison HJ, et al,Lancet,1 thelancet.com/journals/lancet/article/PIIS0140-6736(16)00339-1/fulltext; Esposito S,Longo MR, Autoimmune Rev,2

sciencedirect.com/science/article/pii/S1568997216302178; and van denBerg B, et al, Nat Rev Neurol,3

nature.com/nrneurol/journal/v10/n8/full/nrneurol.2014.121.html.









http://nature.com/nrneurol/journal/v10/n8/full/nrneurol.2014.121.html

http://nature.com/nrneurol/journal/v10/n8/full/nrneurol.2014.121.html


pain are also common residuals. Manypatients experiencing a relatively com-plete recovery from GBS describepersistent fatigue, particularly in theafternoon and evening.39,40 Most ofthe improvement in GBS occurs with-in the first year, but patients maycontinue to improve for up to 3 yearsor longer.1,2 Features of GBS thatpredict a poor prognosis are late ageof onset, preceding diarrhea or C.jejuni infection, the need for intuba-tion and ventilator support within thefirst week of illness, and severeweakness.1Y3 Mortality in GBS is 3%to 7% and is most often attributable torespiratory failure, infection, or uncon-trollable autonomic dysfunction.1Y3

CONCLUSIONGBS has become the most frequentcause of acute or subacute flaccidweakness worldwide.1,2 The illnesspresents with ascending weaknessand areflexia over several days toweeks. The diagnosis requires highdiagnostic suspicion and is usuallysubstantiated by nerve conductionstudy abnormalities and elevated CSFprotein. The illness is treated with IVIgor plasma exchange. Patients withGBS should receive best medicalmanagement, including physical andoccupational therapy, and shouldbe watched closely for respiratorydecompensation, deep venous throm-boses, and decubitus ulcers. Most pa-tients with GBS recover, many makinga complete recovery.

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KEY POINT

h Features ofGuillain-Barre syndromethat predict a poorprognosis are late ageof onset, precedingdiarrhea orCampylobacter jejuniinfection, the need forintubation andventilator supportwithin the first week ofillness, and severeweakness.




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