Guillain-Barre syndrome...Guillain-Barre syndrome Basics database in the UK and found that the relative incidence of GBS within 90 days of influenza immunisation was 0.76 as opposed

Guillain-Barresyndrome

The right clinical information, right where it's needed

Last updated: Nov 20, 2017

Table of ContentsSummary 3

Basics 4

Definition 4

Epidemiology 4

Aetiology 4

Pathophysiology 5

Classification 6

Prevention 7

Secondary prevention 7

Diagnosis 8

Case history 8

Step-by-step diagnostic approach 8

Risk factors 11

History & examination factors 13

Diagnostic tests 16

Differential diagnosis 20

Diagnostic criteria 21

Treatment 25

Step-by-step treatment approach 25

Treatment details overview 27

Treatment options 29

Emerging 35

Follow up 36

Recommendations 36

Complications 36

Prognosis 38

Guidelines 39

Diagnostic guidelines 39

Treatment guidelines 39

References 40

Disclaimer 51

Summary

◊ Acute inflammatory polyneuropathy classified according to symptoms and divided into axonal anddemyelinating forms.

◊ Two-thirds have a history of gastroenteritis or influenza-like illness weeks before onset ofneurological symptoms.

◊ Neurophysiology is confirmatory and is abnormal in 85% of patients, even early in the disease.

◊ Up to 30% will develop respiratory muscle weakness requiring ventilation.

◊ LP is useful, and the classic finding is elevated protein with normal cell count (albuminocytologicaldissociation).

◊ Treatment combines supportive and disease-modifying therapy (plasma exchange or high-doseimmunoglobulin).

Guillain-Barre syndrome BasicsBA

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DefinitionGuillain-Barre syndrome (GBS) is a type of acute inflammatory neuropathy.[1] [2] It is a clinically definedsyndrome characterised by motor difficulty, absence of deep tendon reflexes, paraesthesias withoutobjective sensory loss, and increased CSF albumin with absence of cellular reaction (albuminocytologicaldissociation).[1] [3] Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is the most commonlyencountered variant.[4]

EpidemiologyGBS is identified throughout the western hemisphere without geographical clustering and minor seasonalvariations. Population-based studies give crude mean annual incidence rates varying from 0.6 to 1.9 per100,000 population. Few outbreaks have been reported, including the 1976 outbreak in the US after theswine influenza programme (although the link between the influenza immunisation and incidence of GBS isunclear).[10] [11]

Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is the most common form in westerncountries and accounts for 85% to 90% of cases.[12] [13] This condition occurs at all ages, although rarely ininfancy. Youngest and oldest ages reported are 2 months and 95 years old, respectively.[14] [15] The meanage of onset is approximately 40 years, possibly with a male predominance.[11] [16] There is no consistentage predominance secondary to lack of concordance between studies.[16] GBS is the most common causeof acute flaccid paralysis in children.[17] Acute motor axonal neuropathy (AMAN) is frequently diagnosedin Japan and China, particularly in young people. It occurs more frequently during summer.[18] SporadicAMAN worldwide affects 10% to 20% of patients with GBS.[19] Miller-Fisher syndrome affects between 5%and 10% of GBS patients in western countries, but it is more common in eastern Asia, with 25% occurring inJapan and 19% in Taiwan.[20] [21]

AetiologyThis condition is characterised by an immune-mediated attack on myelin sheath or Schwann cells of sensoryand motor nerves. This is due to cellular and humoral immune mechanisms, frequently triggered by anantecedent infection. Although genetic predisposition has not been fully established, the acute motor axonalneuropathy (AMAN) type of the disease occurs more commonly in Japan and China than in North Americaor Europe. Polymorphisms in macrophage mediators (MMP-9 and TNF-alpha) have been associated withsevere weakness and poorer outcome in GBS patients.[22]

Two-thirds of patients have had infections within the 6 weeks before symptom onset, most commonlyURTI and gastroenteritis. The acute infectious illness is usually viral (CMV, EBV, hepatitis B or C, HIV)or sometimes bacterial ( Campylobacter jejuni , Mycoplasma species). The most commonly identifiedinfectious triggers include C jejuni (in 13% to 39% of cases), CMV (5% to 22%), EBV (1% to 13%),and Mycoplasma pneumoniae (5%).[23] [24] [25] C jejuni infection precedes about 60% to 70% ofAMAN and acute motor-sensory axonal neuropathy (AMSAN) cases and up to 30% of acute inflammatorydemyelinating polyradiculoneuropathy (AIDP) cases.[26] [27] Immunisations have been proposed to triggerGBS, including the no longer used swine influenza vaccines (US in 1976) and the rabies vaccine containingbrain material.[28] [29] However, an epidemiology study found no evidence of increased risk of GBS afterseasonal influenza immunisation.[30] This study looked at 15 years of the General Practice Research

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Guillain-Barre syndrome Basics

database in the UK and found that the relative incidence of GBS within 90 days of influenza immunisationwas 0.76 as opposed to 7.35 within 90 days of influenza-like illness.[30]

Since 2013, several cases of GBS have been reported following the outbreak of Zika virus,[31] [32] possiblysecondary to molecular mimicry, with a proposed putative role for gangliosides.[32] Similarly, several othermosquito-borne viral infections such as dengue, chikungunya, and Japanese encephalitis have been linkedto GBS.[33] [34] [35] [36] [37]

PathophysiologyThere is some evidence to suggest that this condition is an autoimmune disorder. Antibodies to gangliosidesplay an important role. They trigger an attack on various components of peripheral nerve myelin andsometimes even the axons.[38] [39] The mechanism for this is unclear but may be a consequence ofmolecular mimicry, whereby antibodies or T cells stimulated by antigenic epitopes on the infecting microbecross-react with neural epitopes.[40] Host-generated antibodies against GM1-, GD1a-, GalNac-Gd1a-, andGD1b-related gangliosides are strongly associated with a subtype of AMAN, AMSAN, and Miller-Fishersyndrome, respectively.[15] [18] [41] [42] [43] [44] [45] AMAN is strongly associated with antibodies againstGM1, GD1a, GalNac-GDa1, and GD1b.[41] [42] [46] [47]

Pure sensory GBS may be associated with antibodies to GD1b.[9] Ganglioside complexes have been foundto influence the phenotype. Antibodies against GD1a/GD1b or GD1b/GT1b may cause severe GBS, andantibodies against complexes containing GQ1b or GT1a are more likely to cause ophthalmoplegia in bothGBS and Fisher syndrome patients.[48] However, large-scale prospective studies are required to confirmthis. Antibodies against neurofascin, a protein present at the node of Ranvier, have been described in a smallproportion (4%) of patients with GBS.[49]

In C jejuni -related infections, carbohydrate mimicry between the bacterial capsular lipooligosaccharide andspecific myelin gangliosides and glycolipids is thought to induce antibodies against myelin.[50] [51]

An immune cascade occurs in AIDP with early lymphocytic infiltrates in spinal roots and peripheral nerves.Subsequent macrophage-mediated segmental stripping of myelin occurs.[15] This leads to segmentaldemyelination and mononuclear cellular infiltration.[4] Segmental loss of the insulating properties causesprofound defects in the propagation of electrical nerve impulses, resulting in conduction block and thefunctional correlate of flaccid paralysis.[52] Once the immune reaction stops, repair and remyelinationpromptly begin, which correlate with a quick and, in most cases, complete recovery from the flaccidparalysis.[15]

AMAN can be differentiated from AIDP by autopsy findings of axonal denervation of motor and sensorynerves with no demyelination and minimal inflammation.[53] [54] The earliest demonstrable pathologicalchange seems to be the binding of IgG and activated complement components to axolemma at nodes ofRanvier in large motor fibres.[55] Macrophages become attracted to these nodes and track underneath thedetached myelin lamellae along the periaxonal space. This dissects the axon from the overlying Schwann celland compact myelin. Axolemmas in contact with invading macrophages are focally destroyed, while axonsshow progressive denervative changes to the point of total disintegration.[54] C jejuni strains associatedwith the AMAN pattern of GBS are known to have GM1-like epitopes in the liposaccharide membrane.[7]Pathological studies suggest severe and selective loss of terminal motor axons, whereas the distal sensoryfibres are completely intact.[56] [57]

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This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Nov 20, 2017.BMJ Best Practice topics are regularly updated and the most recent versionof the topics can be found on bestpractice.bmj.com . Use of this content is


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Guillain-Barre syndrome BasicsBA

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ClassificationVariants of Guillain-Barre[2]GBS is classified according to symptoms and is divided into axonal and demyelinating forms.

• Sensory and motor: AIDP (most common) or acute motor-sensory axonal neuropathy (AMSAN).• Motor: acute motor demyelinating neuropathy (AMDN) or acute motor axonal neuropathy (AMAN)

• Miller-Fisher syndrome: ophthalmoplegia, ataxia, and areflexia (also referred to as Fisher'ssyndrome).

• Bickerstaff's brainstem encephalitis (BBE): similar to Miller-Fisher syndrome but also includes alteredconsciousness (encephalopathy) or long tract signs (hyper-reflexia), or both.[5]

• Pharyngeal-cervical-brachial: acute arm weakness, swallowing dysfunction, and facial weakness.[6]• Acute pandysautonomia: diarrhoea, vomiting, dizziness, abdominal pain, ileus, orthostatic hypotension

and urinary retention, bilateral tonic pupils, fluctuating heart rate, decreased sweating, salivation, andlacrimation.[7] [8]

• Pure sensory: acute sensory loss, sensory ataxia, and areflexia but no motor involvement.[9]




Guillain-Barre syndrome Prevention

Secondary preventionNo definite preventative action is recommended. However, immunisation is not recommended during theacute phase of GBS and is not suggested for a period of ≥1 years after the onset. After 1 year the need forimmunisation should be reviewed on an individual basis.

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Guillain-Barre syndrome DiagnosisD

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Case historyCase history #1A 20-year-old woman with no significant past medical history presents with lower back pain and bilateralfoot and hand tingling. Her symptoms rapidly progress over 4 days to include lower extremity weakness tothe point that she is unable to mobilise her lower extremities. She reports coryzal symptoms 2 weeks ago.On examination, she has 0/5 power in her lower extremity with areflexia, but despite the paraesthesiasshe does not have sensory deficits. Her aminotransferases are elevated, and LP reveals mildly elevatedprotein with no cells and normal glucose. She weighs 70 kg and her admission vital capacity is 1300 mL,maximum inspiratory pressure is -30 cmH2O, and maximum expiratory pressure is 35 cmH2O.

Step-by-step diagnostic approachDiagnosis is made by pattern recognition.[76] The classic presentation is a progressive symmetrical muscleweakness affecting lower extremities before upper extremities, and proximal muscles before distal muscles,accompanied by paraesthesias in the feet and hands.[77] [78] The paralysis is typically flaccid with areflexiaand progresses acutely over days, with 73% reaching a lowest point within 1 week and 98% by 4 weeks.[58]The progressive phase is followed by a plateau phase of persistent, unchanging symptoms lasting a variableduration before recovery begins. Mild dysautonomia occurs in 70% and causes sinus tachycardia, labile BP,postural hypotension, urinary retention, ileus, and very rarely life-threatening cardiac arrhythmia.

Initial tests include LP, spirometry, neurophysiological evaluation, and hepatic aminotransferases.

HistoryTwo-thirds of patients have a history of influenza-like or respiratory illness or gastroenteritis within 6weeks before onset of neurological symptoms.[11] [58] The most commonly presenting symptoms includea respiratory tract or GI tract infection that has resolved by the time neurological symptoms begin, whichis around 1 to 3 weeks (mean 11 days in several large studies) after the initial illness.[11]

Other anecdotal triggers include history of trauma, surgical procedures, immunisations, malignancy, andHIV infection. GBS is more common in the older age groups and in males.

Since 2013, several cases of GBS have been reported following the outbreak of Zika virus.[31] [32]Similarly, several other mosquito-borne viral infections such as dengue, chikungunya, and Japaneseencephalitis have been linked to GBS.[33] [34] [35] [36] [37]

Symptoms and signsParaesthesias in hands and feet frequently precede the onset of weakness.[10] These are usually mildand may extend proximally in the extremities. About 89% of patients experience pain, which typicallybegins in the back and legs. It occurs at onset and during disease course.[79] Presence of back pain andparalysis is easily misinterpreted as cord compression, precipitating unnecessary surgical intervention.In children, pain is a much more prominent symptom compared to adults.[80] Hyporeflexia or areflexiacan be seen at the onset in both GBS and cord compression, but the presence of bowel or bladderdysfunction early on or the finding of a sensory level should alert one to the prospect of acute myelopathy.




Guillain-Barre syndrome Diagnosis

Facial, oropharyngeal, and extraocular weakness may also occur.[10] These cranial nerve deficits oftenoccur after trunk and limb involvement but precede them in 15%.[10]

Mild dysautonomia is common and results in sinus tachycardia, HTN, and postural hypotension. Otherautonomic symptoms such as urinary retention and ileus can happen in up to one quarter of patients.[81]Life-threatening cardiac arrhythmias are relatively rare.[10] [82] Up to 30% will develop respiratory muscleweakness requiring mechanical ventilation.[83] In children, autonomic dysfunction may be an independentrisk factor for mechanical ventilation.[80] Typical complaints may include dyspnoea on exertion and SOB.

Acute inflammatory demyelinating polyradiculoneuropathy(AIDP)Typical symptoms include acute polyradiculoneuropathy, causing progressive weakness of 2 or morelimbs with reduced or absent tendon reflexes.[77] Time of onset is not more than 4 weeks, and alternativeaetiologies should be absent.[77] Symptoms are predominantly proximal but may affect distal musclesas well. There may be motor, sensory, or mixed disturbances, with or without autonomic features. Theseusually follow an antecedent influenza-like illness, or respiratory or GI infection.[15] [39] [84]

Acute motor axonal neuropathy (AMAN)AMAN presents as acute weakness or paralysis without any sensory loss and with reduced or absentreflexes. Most cases are preceded by Campylobacter jejuni infection.[18] [85] It is distinguished fromAIDP by selective involvement of motor nerves, preservation of sensory fibres, and electrophysiologyshowing axonal features. AMAN has a more rapid progression and earlier lowest point than AIDP.[18] [86]

Acute motor-sensory axonal neuropathy (AMSAN)This is associated with sensory and motor deficits with axonal loss.[27] [87] It often presents withfulminant paralysis and sensory loss with incomplete recovery.[53]

Bickerstaff's brainstem encephalitis (BBE)Clinical features are similar to Miller-Fisher syndrome but also include altered consciousness(encephalopathy) or long tract signs (hyper-reflexia), or both.[5] BBE may be a separate clinical entitysecondary to its clinical features of drowsiness, coma, hyper-reflexia, and extensor plantar responses.[88]Alternatively, it may also be a variant of Miller-Fisher syndrome.[89] [90] If the Miller-Fisher syndrometriad presents with drowsiness and extensor plantar response, BBE is the likely underlying diseaseprocess.[83] [91]

Pharyngeal-cervical-brachialThis presents with acute arm weakness, swallowing dysfunction, and facial weakness.[6]

Miller-Fisher syndrome (MFS)This is characterised by impaired eye movements (ophthalmoplegia), abnormal coordination (ataxia), andloss of tendon reflexes (areflexia).[20] Occasionally ophthalmoplegia may be absent.[92] It does not causelimb or respiratory muscle weakness.[39] Pupillary abnormalities, ptosis, and bulbar and facial palsy mayoccur.[93] It is usually a self-limiting, benign condition.[93] Occasionally, patients may have limb weaknesswith a MFS-GBS overlap syndrome, which has similar prognosis to that of GBS. Overlap syndromessuch as the pharyngeal-cervical-brachial variant of GBS or BBE can occur in 50% of patients with MFS

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within the first week of onset of MFS.[94] The median period between neurological symptom onset andthe disappearance of ataxia/ophthalmoplegia is between 32 and 88 days.[93]

Acute pandysautonomiaPresenting symptoms and signs include diarrhoea, vomiting, dizziness, abdominal pain, ileus, orthostatichypotension, and urinary retention. GBS may be associated with bilateral tonic pupils and may involveboth parasympathetic and sympathetic postganglionic neurons.[8] Patients with Miller-Fisher syndromemay also have bilateral tonic pupils.[95] [96] Up to nearly half of patients with Miller-Fisher syndromehave sluggish pupils and mydriasis.[93] [96] Other signs of dysautonomia, including fluctuating heart rate,decreased sweating, salivation, and lacrimation, may be present.[7]

Pure sensoryThis presents with acute sensory loss, sensory ataxia, and areflexia but no motor involvement.[9] It mostlyaffects the large sensory fibres, and may be associated with antibodies to GD1b.[9]

InvestigationsIf the diagnosis remains unclear despite clinical examination, anti-ganglioside antibodies, CSF analysis,and electrodiagnostical tests can be performed to differentiate subtypes.[83] [97] [98] In practice, GQ1B isthe only antibody routinely tested to diagnose Miller-Fisher syndrome.

Neurophysiological evaluationNerve conduction studies are routinely performed and play an important role in diagnosis, subtypeclassification, and confirming that the disease is a peripheral neuropathy. There is no consensus on theneurophysiological criteria for classification, and neither are there any data on when it should be done;nevertheless, it should be done as soon as possible.[77] [78] [83] [99] [100] At least 3 sensory nerves and3 motor nerves with multisite stimulation F waves and bilateral tibial H reflexes need to be evaluated.[83]

Early studies may be normal in 13% of examinations, but few remain normal with serial testing 1 to 2weeks apart.[99] Early abnormalities typically include prolonged distal and F-wave latencies and reducedconduction velocities. H reflex is also prolonged or absent.[83] Evidence of demyelination is present in85% of patients with early testing.[99]

Very reduced or absent evoked responses on distal supramaximal stimulation of motor and sensorynerves have been demonstrated. This progresses rapidly to total loss of electrical excitability consistentwith axonal degeneration.[101] A positive test will at least help localise the disease process to theperipheral nervous system. If it is persistently normal despite severe deficits, the disease process maybe in muscle, neuromuscular junction, spinal cord, or higher. A paradox of small median sensory actionpotentials with retained sural responses has been described in GBS.[102]

CSF analysisCSF analysis is an important laboratory aid in excluding other infectious causes and should be performedearly for this reason. Elevated CSF protein with normal cell count (albuminocytological dissociation) isthe classic finding, which occurs in up to 90% at 1 week after symptom onset. However, CSF proteinmay be normal during the first week of the illness, and repeat LP is warranted if the diagnosis remains inquestion.[62] [103] A retrospective study has suggested a correlation between the level of CSF proteinelevation and the amount of electrophysiologically demonstrable demyelination.[104]





If CSF pleocytosis is present, further evaluation for HIV, Lyme disease, sarcoidosis, meningitis, orcarcinomatous meningitis should be initiated.[83] [91] These tests would include HIV enzyme-linkedimmunosorbent assay (ELISA), Lyme serology and Western blot, CSF Lyme antibody, CSF ACE and aCXR, CSF VDRL, CSF cytology and flow cytometry, CSF Gram stain, CSF culture, and CSF West NilePCR. Further viral studies should be considered if immunosuppression is a concern.

[VIDEO: Diagnostic lumbar puncture animated demonstration ]

SpirometryBedside spirometry should be performed every 6 hours initially. This will help triage the patient tothe ICU or the regular ward. A forced vital capacity of <20mL/kg is an indication for ICU admission.Patients with bulbar dysfunction and high risk of aspiration should be intubated for airway protection andimpending respiratory failure. Risk factors for progression to mechanical ventilation include rapid diseaseprogression, bulbar dysfunction (odds ratio 17.5), bilateral facial nerve weakness, and dysautonomia.[108][109] Other risk factors include inability to lift head (odds ratio 5.0) or inability to cough (odds ratio9.09).[110] Pulse oximetry and ABGs should not be relied on, as either hypoxia or hypercarbia are latesigns and patients will decompensate very quickly.

Serology and stool cultureAn increase in titres for infectious agents including CMV, EBV, Mycoplasma , Haemophilus influenzae ,and C jejuni may help in establishing aetiology for epidemiological purposes but is of limited clinical use.Some data suggest that positive serological markers for C jejuni are associated with worse prognosticoutcome.[24] [111] Testing for C jejuni may be considered if there is an antecedent history of diarrhoeaor being in a region where AMAN is prevalent. Treatment with antibiotics may be indicated if there ispersistent faecal excretion of the bacteria. If clinical features suggest a less common variant, particularlyMiller-Fisher variant or pharyngeal-cervical-brachial variant, then testing for anti-ganglioside antibodiesanti-GQ1b and anti-GT1a, respectively, may have some diagnostic utility. Anti-GQ1b IgG antibodiesare found in 90% of patients with Miller-Fisher syndrome. The evidence for clinical utility of other anti-ganglioside antibodies remains less robust.[112] [113]

Hepatic aminotransferasesHepatic aminotransferases may be elevated during the first few days in 10% to 20% with GBS and oftennormalise by 1 to 2 weeks. Presence of elevated liver enzymes also correlates with increased severityof disease and should be routinely tested and monitored.[14] [114] If transaminases remain persistentlyelevated, evaluation for viral hepatitides should be considered.

ImagingSpinal MRI may be useful when the diagnosis is unclear and electrophysiological abnormalities areequivocal. It can also be performed to exclude disease process involving the spinal cord (i.e., epiduralabscess, transverse myelitis, spinal stenosis, spinal cord stroke, or tumour). Brain magnetic imagingabnormalities are present in 30% of patients with BBE.[89]

Risk factorsStrong

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preceding viral illness• Two-thirds have a history of gastroenteritis or influenza-like illness within the weeks before onset of

neurological symptoms.[11] [58]

preceding bacterial infection• Studies have found that about 60% to 70% of acute motor axonal neuropathy (AMAN) and acute

motor-sensory axonal neuropathy (AMSAN) cases and up to 30% of acute inflammatory demyelinatingpolyradiculoneuropathy (AIDP) cases are preceded by Campylobacter jejuni infection.[26] [27] Campylobacter -associated GBS appears to have a worse prognosis, manifested by slower recoveryand greater residual neurological disability.[12] A study in Sweden estimated that the risk of developingGBS during the 2 months following C jejuni infection is approximately 100-fold higher.[59]

preceding mosquito-borne viral infection• Since 2013, several cases of GBS have been reported following the outbreak of Zika virus.[31] [32]

Similarly, several other mosquito-borne viral infections such as dengue, chikungunya, and Japaneseencephalitis have been linked to GBS.[33] [34] [35] [36] [37]

Weakimmunisation• In the US an increased risk of GBS was associated with the swine influenza vaccine in 1976, although

the severity of the risk has been controversial. Subsequently no increased risk was observed upto 1991.[10] Carefully conducted surveillance studies of subsequent mass influenza immunisationprogrammes of the US Army found no increased incidence of GBS.[60] An epidemiology study foundno evidence of increased risk of GBS after seasonal influenza immunisation.[30] This study looked at15 years of the General Practice Research database in the UK and found that the relative incidenceof GBS within 90 days of influenza immunisation was 0.76, as opposed to 7.35 within 90 days ofinfluenza-like illness.[30] However, it is thought that modern influenza vaccination produces <1 caseper million recipients.[61]

• Eight cases of GBS that occurred after meningococcal conjugate vaccine A, C, Y, and W135 (MCV4)have been reported. The correlation is still doubtful because the rate of GBS within 6 weeks afterimmunisation is the same as by chance.[62]

• The possibility that GBS might be triggered by live, attenuated oral poliovirus vaccine was suggestedin a report from Finland.[63]

• The occurrence of GBS is about 1 in 1000 cases following rabies vaccine containing murine myelin, anantibody response to human myelin basic protein and galactocerebroside.[29]

• One systematic review estimated the risk of GBS at 1.6 excess cases per million people vaccinated,but it concluded that this risk should be weighed against the protective benefits of vaccination.[64]

cancer and lymphoma• Case reports often link GBS with Hodgkin's disease.[65] Less commonly, other malignancies have

also been associated with GBS. These include oat cell carcinoma, adenocarcinoma of the lung, smallcell lung cancer, and chronic lymphocytic leukaemia.[66] [67] [68] [69]





older age (mean 40 years)• Incidence increases with age. For people <30 years of age, the incidence is <1:100,000. For people

>75 years of age, incidence is 4:100,000.[24] [58] The mean age of onset is approximately 40years.[11] [16]

HIV infection• Anecdotal: several cases have been reported in patients with HIV and GBS.[70] [71] [72] [73] [74]

male• Male-to-female ratio varies from 1.0:1.0 to 1.9:1.0.[16] [75]

History & examination factorsKey diagnostic factorspresence of risk factors (common)• Key risk factors include preceding viral or bacterial infection.

muscle weakness (common)• Progressive symmetrical muscle weakness usually affecting lower extremities before upper extremities

and proximal muscles before distal muscles accompanied by paraesthesias in the feet and hands.[77][78] The paralysis is typically flaccid with areflexia and progresses acutely over days with 50%reaching a lowest point within 1 week and 98% by 4 weeks.[58] Weakness evolving for >4 to 8 weeksis more consistent with chronic inflammatory demyelinating polyradiculoneuropathy.[77] [78]

respiratory distress (common)• Typical complaints may include dyspnoea on exertion and SOB, but respiratory muscle weakness can

often be asymptomatic. Up to 30% will develop respiratory muscle weakness requiring mechanicalventilation.[62]

speech problems (common)• Facial weakness and oropharyngeal weakness occurs in 50% of patients.[62] Typical complaints

include slurred speech.

paraesthesia (common)• Paraesthesias in hands and feet occur in 80% of patients and frequently precede the onset of

weakness.[59] These may extend proximally in the extremities, but sensory abnormalities onexamination are usually mild. If a distinct sensory level is noted on examination, this is unlikely to beGBS and more likely a spinal cord process.

back/leg pain (common)• Pain occurs in approximately 89% of patients at onset and during the course of the disease,

and typically begins with back and leg pain.[79] Presence of back pain and paralysis is easilymisinterpreted as cord compression.

• In children, pain is a much more prominent symptom compared to adults.[80]

areflexia/hyporeflexia (common)

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• Approximately 65% are entirely areflexic on admission, 90% can have absent ankle jerks, and 80%have absent knee jerk, while 10% may have absent reflexes only in the weakest limbs.[114] Plantarreflex should be downgoing or absent but never upgoing. Tone should be flaccid.

facial weakness (common)• Occurs in 50% of patients.[62]

bulbar dysfunction causing oropharyngeal weakness (common)• Together with bilateral facial weakness, bulbar dysfunction is associated with increased risk of

progression to mechanical ventilation.[108] Oropharyngeal weakness occurs in 50% of patients.[62]Typical complaints include swallowing difficulty.

extra-ocular muscle weakness (common)• Occurs in 15% of patients.[62]

facial droop (common)• Often occurs after trunk and limb involvement but occurs before in about 15% of patients.[62]

diplopia (common)• Often occurs after trunk and limb involvement but occurs before in about 15% of patients.[62]

dysarthria (common)• Often occurs after trunk and limb involvement but occurs before in about 15% of patients.[62]

dysphagia (common)• Often occurs after trunk and limb involvement but occurs before in about 15% of patients.[62]

dysautonomia (common)• Mild dysautonomia is common and results in sinus tachycardia, HTN, and postural hypotension in

approximately two-thirds of patients. Other autonomic symptoms such as urinary retention and ileuscan happen in up to one quarter of patients.[81] Bladder disturbance is usually mild or absent early inthe disease, and if severe, cord compression should be excluded. Life-threatening cardiac arrhythmiasare relatively rare.[10] [82]

• Autonomic dysfunction in children may be an independent risk factor for mechanical ventilation.[80]

anisocoria (uncommon)• If it occurs, tends to accompany severe ophthalmoparesis and ptosis.[115]

non-reactive pupil (uncommon)• Although uncommon, light-fixed dilated pupils in GBS have been described.[116] [117] If pupils are

fixed and dilated, the possibility of botulism needs to be considered as this is a typical finding.• GBS may be associated with bilateral tonic pupils and may involve both parasympathetic and

sympathetic post-ganglionic neurons.[8] Up to nearly half of patients with Miller-Fisher syndrome havesluggish pupils and mydriasis.[93] [96]

ophthalmoplegia (uncommon)





• Ataxia, areflexia, and ophthalmoplegia are the classic triad for Miller-Fisher syndrome.[20] [87] [118]Around 30% of patients with Miller-Fisher syndrome may develop extremity weakness manifesting asan overlapping syndrome with classic GBS.

Other diagnostic factorsptosis (common)• May occur in Miller-Fisher syndrome.

altered level of consciousness (common)• Encephalopathy and hyper-reflexia may be the presenting features of Bickerstaff's brainstem

encephalitis (BBE), which may be a variant of Miller-Fisher syndrome.

ataxia (uncommon)• Characteristic feature of Miller-Fisher syndrome. A few patients with Miller-Fisher syndrome present

with ataxia and hyporeflexia without ophthalmoplegia.[20]

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Diagnostic tests1st test to order

Test Resultnerve conduction studies

• Interpretation of electrophysiology can be difficult, especially in earlystages. However, clear electrophysiological evidence of demyelinatingpolyneuropathy is useful for outcome prediction.[99] Different sets ofcriteria have been published, including the following:

• Acute inflammatory demyelinating polyradiculoneuropathy (AIDP):patchy demyelination, slowing of motor nerve conduction velocities,prolonged distal and F-wave latencies, and dispersed response onneedle.[15] [84]

• At least 1 of the following in 2 nerves, or at least 2 of the following in1 nerve: motor conduction velocity (MCV) <90% lower limit of normal(LLN; 85% if distal compound muscle action potential [dCMAP] <50%LLN), distal motor latency (DML) >110% upper limit of normal (ULN;>120% if dCMAP <100% LLN), pCMAP/dCMAP ratio <0.5% anddCMAP >20% LLN, F-response latency >120% ULN.

• Newer criteria have been proposed for AIDP, which increase thesensitivity of diagnosis, and include:[119]

• • at least 1 of the following in at least 2 nerves: MCV <70% LLN; DML>150% ULN; F-response latency >120% ULN, or >150% ULN (ifdistal CMAP <50% of LLN); or

• • F-wave absence in 2 nerves with dCMAP ≥20% LLN or greater, withan additional parameter, in 1 other nerve; or

• • pCMAP/dCMAP ratio <0.7 (excluding the tibial nerve) in 2 nerves,with an additional parameter in 1 other nerve.

• Acute motor-sensory axonal neuropathy (AMSAN): diminution ofmuscle and sensory action potentials.[53] None of the features ofAIDP except 1 demyelinating feature allowed in 1 nerve if dCAMP<10% LLN and sensory action potential amplitudes less than LLN.

• Acute motor axonal neuropathy (AMAN): reduction in distally evokedmotor action potential amplitudes, early signs of denervation onneedle, normal action potential on sensory nerves, and relativelypreserved motor nerve conduction velocity.[39] [56] [57] None of thefeatures of AIDP except 1 demyelinating feature allowed in 1 nerve ifdCMAP <10% LLN and sensory action potential amplitudes normal.

• Miller-Fisher syndrome: reduced or absent sensory action potentialresponse without slowing of sensory conduction velocity.[120]

slowing of nerveconduction velocities





Test ResultLP

• Classic finding is elevated CSF protein with normal cell count(albuminocytological dissociation). Occurs in up to 90% at week 1after symptom onset. CSF protein is usually normal within the first 2to 3 days but then begins to rise very quickly, reaching a peak at 4to 6 weeks and then persisting at a variably elevated level for manyweeks.[121]

• CSF protein level varies from 0.45 to 3.0 g/L (45-300 mg/dL), butlevels as high as 10 g/L (1000 mg/dL) can be seen.[122] Around59% of patients with Bickerstaff's brainstem encephalitis (BBE) haveelevated protein in CSF.[89] [90]

• Extremely high protein levels (10 g/L [1000 mg/dL]) are associatedwith development of high intracranial pressure and papilloedema.Around 10% will not have a protein elevation and this includespatients with the Miller-Fisher variant.[123] [124] Cell counts aretypically <5 cells/mm^3. However, in 10% of patients, lymphocytosis<50 cells/mm^3 may be present early on but quickly normalises overa few days.[121]

[VIDEO: Diagnostic lumbar puncture animateddemonstration ]

elevated CSF protein,normal/slightly highlymphocytes (<50 cells/mm^3)

LFT• Hepatic aminotransferases may be elevated during the first few

days in 10% to 20% of patients and often rapidly normalise by 1 to 2weeks.[14] Elevation of hepatic enzymes is associated with a moresevere disease.[114] The cause is unclear. EBV and CMV infectionhave been suggested, but serological markers are often negative.

elevated AST and ALT ashigh as 500 U/L; bilirubinmay be transientlyelevated but rarely highenough to cause jaundice

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Test Resultspirometry

• Should be carried out at 6-hour intervals initially at the bedside.ICU monitoring and elective intubation should be considered if: vitalcapacity is <20 mL/kg (odds ratio 15.0); maximal inspiratory pressureworse than -30 cmH2O; maximal expiratory pressure <40 cmH2O;reduction of 30% in vital capacity, maximal inspiratory pressure, ormaximal expiratory pressure.[108]

[VIDEO: Tracheal intubation animateddemonstration ]

[VIDEO: Bag-valve-mask ventilation animateddemonstration ]

may show reducedvital capacity, maximalinspiratory pressure,or maximal expiratorypressure

antiganglioside antibody• Presence of subtype-specific antiganglioside antibodies can

differentiate between subtypes and may be useful when the diagnosisremains unclear despite clinical examination, CSF analysis, andelectrodiagnostic tests.[83] [97] [98] In practice, GQ1b is the onlyantibody routinely tested to diagnose Miller-Fisher syndrome.Antibodies are present in 85% to 90% of patients with Miller-Fishersyndrome.[83] It has 90% sensitivity and is also present in pharyngo-cervical-brachial GBS variant, Bickerstaff's brainstem encephalitis(BBE), and overlap syndromes. The epitopes are expressedspecifically in the nodal regions of oculomotor nerves, in dorsal rootganglion cells, and cerebellar neurons.[128] GQ1b IgG antibodies arepresent in 96% of patients;[15] [21] [87] [113]

• 66% BBE patients have anti-GQ1b antibodies.[89] [90]• Pharyngo-cervical-brachial may be associated with IgG and GT1

antibodies.[112] [129]

Acute motor-sensoryaxonal neuropathy(AMSAN): GM1, GM1b,GD1a; acute motor axonalneuropathy (AMAN): GM1,GM1a, GD1a, GalNac-GD1a; Miller-Fishersyndrome: GQ1b, GT1aGQ1b; Miller-Fishersyndrome/GBS overlapsyndrome: GQ1b, GM1,GM1a, GD1a, GalNac-GD1a; acute inflammatorydemyelinatingpolyradiculoneuropathy(AIDP): antibodiesunknown; Miller-Fishersyndrome/GBS overlapsyndrome: GQ1*, GM1,GM1a, GD1a, GalNac-GD1a

Other tests to consider

Test Resultserology

• An increase in titres for infectious agents including CMV, EBV, Mycoplasma , H influenzae , and C jejuni may help in establishingaetiology for epidemiological purposes but is of limited clinical use.Some data suggest that positive serological markers for C jejuni areassociated with worse prognostic outcome.[24] [111]

• Bickerstaff's brainstem encephalitis (BBE) may have antecedentinfection in 92%.[89] [90]

presence ofCampylobacter jejuni ,CMV, EBV, Mycoplasmapneumoniae , orHaemophilus influenzae

stool culture• Testing for C jejuni may be considered if there is an antecedent

history of diarrhoea or in a region where acute motor axonalneuropathy (AMAN) is prevalent.

presence ofCampylobacter jejuni orpoliovirus (pure motorsyndrome)



http://bestpractice.bmj.com/procedural-videos/en-gb/67fc9278-908e-48af-8752-085b1de23b79


http://bestpractice.bmj.com/procedural-videos/en-gb/129b1e64-893a-4a65-b198-d27e27f17088




Test ResultHIV antibodies

• High-risk person or presence of CSF lymphocytic pleocytosis (>10cells/mm^3).

positive in HIV infection

spinal MRI• Sensitive but non-specific.• Enhancement of the cauda equina nerve roots with gadolinium

has been found to be 85% sensitive for acute GBS and present in95% of typical cases.[110] May be useful when diagnosis is unclearand electrophysiological abnormalities are equivocal. Can excludedisease processes involving the spinal cord (i.e., epidural abscess,transverse myelitis, spinal stenosis, spinal cord stroke, or tumour). Ina study of 24 patients with GBS scanned on day 13, enhancement ofthe cauda equina nerve roots with gadolinium on lumbosacral MRIwas found to be 83% sensitive for acute GBS and was present in95% of typical cases.[130]

may show enhancementof cauda equina nerveroots with gadolinium

Borrelia burgdorferi serology• Should be performed early to aid exclusion of other causes.

positive in Lyme disease

CSF meningococcal PCR• Should be performed early to aid exclusion of other causes.

positive in meningococcalmeningitis

CSF cytology• Should be performed early to aid exclusion of other causes.

positive in carcinomatousmeningitis

CSF ACE• Should be performed early to aid exclusion of other causes.

positive in sarcoidosis

CXR• Should be performed early to aid exclusion of other causes.

bihilar lymphadenopathyin sarcoidosis

CSF VDRL• Should be performed early to aid exclusion of other causes.

positive in neurosyphilis

CSF West Nile PCR• Should be performed early to aid exclusion of other causes.

positive in West Nile virusinfection

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Differential diagnosis

Condition Differentiating signs /symptoms

Differentiating tests

Transverse myelitis • Spinal cord disordersincluding transverse myelitispresent with asymmetricalmotor or sensory lossusually involving lowerextremities, early bowel orbladder dysfunction withpersistent incontinence, andsegmental radicular pain.

• Physical examinationdemonstrates upper motorneuron signs (hyperreflexia,positive Babinski's response)and a sensory level.

• CSF analysis: pleocytosiswith modest number oflymphocytes and increase intotal protein.

• MRI shows focaldemyelination with possibleenhancement at theappropriate level.[62]

Myasthenia gravis • Early involvement of musclegroups including extra-ocular, levator, pharyngealjaw, neck, and respiratorymuscles. Sometimespresents without limbweakness.

• Excessive fatigability andvariation of symptoms andsigns through the day iscommon.

• Reflexes are preserved,and sensory features,dysautonomia, and bladderdysfunction are absent.

• Electrophysiological studyshows normal nerveconduction and presenceof decremental response torepetitive nerve stimulation.

• EMG shows abnormal jitterand blocking.

• Edrophonium test is normallypositive.[124] However,many centres do notroutinely perform this testbecause of potential sideeffects.

Lambert-Eatonmyasthenic syndrome(LEMS)

• Can be difficult todifferentiate becauseof similar clinicalcharacteristics. However,some characteristics aremore typical for LEMS.These include slowerdevelopment of clinicalsymptoms, dry mouth,lack of objective sensoryloss, rare involvementof respiratory musclegroup, and potentiation ofreflexes after exercise orcontraction.[124]

• Electrophysiological study:hallmark is a low amplitudecompound muscle actionpotential (CMAP) after singlenerve stimulus, increasein CMAP amplitude aftervoluntary contraction, orrepetitive stimulation at highfrequencies.[124]





Condition Differentiating signs /symptoms

Differentiating tests

Botulism • History of ingesting foodtainted with botulinum toxin.

• Descending paralysis beginsin the bulbar muscles thenthe limbs, face, neck, andrespiratory muscles.

• Respiratory muscles areinvolved with mild limbweakness, and reflexes areusually preserved.

• Ptosis, dilated non-reactivepupils are present. Dilatednon-reactive pupils areuncommon in GBS, but morecommon in botulism.

• Constipation is also acharacteristic feature ofbotulism.[124]

• Electrophysiological study:reduced amplitude ofevoked muscle potentials,increase in amplitude withrepetitive nerve stimulation,and increased number ofmyopathic units, which isatypical for GBS.[124]

Polymyositis • Presence of pain and muscletenderness usually in theshoulder and upper arm,involvement of flexor neckmuscle disproportionate tolimb weakness, absenceof sensory symptoms,preservation of reflexes,absence of dysautonomia,and presence of skin lesions,which are uncommonpresentation for GBS.[124]

• Elevated ESR and CK,normal nerve conductionstudy, and myopathicchanges with fibrillation onEMG.

• Muscle biopsy showsmuscle fibre destructionand regeneration, andlymphocyte infiltrates.[124]

Vasculitic neuropathy • Common features includepainful asymmetricalpresentation of muscleweakness, uncommoninvolvement of cranialnerves, respiratory paralysis,and sphincter dysfunction.

• Usually patients complain offever, fatigue, weakness, andarthralgia.[124]

• May have elevated ESR.• CSF does not show

albuminocytologicaldissociation.

• Electrophysiologicalstudy shows evidence ofdenervation.

• Nerve biopsy showssigns of inflammation andscarring.[124]

Diagnostic criteriaAssessment of current diagnostic criteria for Guillain-Barresyndrome[77]Required features

• Progressive weakness in both arms and legs• Areflexia (or hyporeflexia).

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Features supportive of diagnosis

• Progression of symptoms over days to 4 weeks• Relative symmetry• Mild sensory signs or symptoms• Cranial nerve involvement, especially bilateral facial weakness• Recovery beginning 2 to 4 weeks after progression ceases• Autonomic dysfunction• Absence of fever at onset• Typical CSF and EMG/nerve conduction studies features.

Features casting doubt on the diagnosis

• Asymmetrical weakness• Persistent bladder and bowel dysfunction• Bladder or bowel dysfunction at onset• >50 mononuclear leukocytes/mm^3 or presence of polymorphonuclear leukocytes in CSF• Distinct sensory level.

Features that rule out the diagnosis

• Hexacarbon abuse• Abnormal porphyrin metabolism• Recent diphtheria infection• Lead intoxication• Other similar conditions: poliomyelitis, botulism, hysterical paralysis, toxic neuropathy.

Electrophysiological classification of Guillain-Barre syndrome[99]Neurophysiological criteria for acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor-sensory axonal neuropathy (AMSAN), and acute motor axonal neuropathy (AMAN).[83] [99]

At least 3 sensory nerves and 3 motor nerves with multi-site stimulation F waves, and bilateral tibial Hreflexes, need to be evaluated.[83]

AIDP

At least 1 of the following in each of at least 2 nerves, or at least 2 of the following in 1 nerve if all othersinexcitable and distal compound muscle action potential (dCMAP) >10% lower limit of normal (LLN):

• Motor conduction velocity <90% LLN (85% if dCMAP <50% LLN)• Distal motor latency >110% upper limit of normal (ULN) (>120% if dCMAP <100% LLN)• pCMAP/dCMAP ratio <0.5 and dCMAP >20% LLN• F-response latency >120% ULN.

AMSAN

• None of the features of AIDP except 1 demyelinating feature allowed in 1 nerve if dCMAP <10% LLN• Sensory action potential amplitudes less than LLN.

AMAN





• None of the features of AIDP except 1 demyelinating feature allowed in 1 nerve if dCMAP <10% LLN• Sensory action potential amplitudes normal.

Inexcitable

• dCMAP absent in all nerves or present in only 1 nerve with dCMAP <10%.

Electrodiagnostic criteria for acute and chronic inflammatorydemyelinating polyradiculoneuropathy[100]Different sets of criteria have been published, including the following (sensitivity 64% to 72%):

• 150% prolongation of motor distal latency above ULN• 70% slowing of motor conduction velocity below LLN• 125% (150% if the distal negative-peak CMAP amplitude was 80% of LLN) prolongation of F wave

latency above ULN• Abnormal temporal dispersion (peak CMAP duration increase) in ≥2 nerves.

Diagnostic and classification criteria for the Guillain-Barresyndrome[78]Necessary criteria for clinical diagnosis:[78]

• Sub-acutely developing flaccid paralysis over <4 weeks• Symmetrical weakness from the onset of the symptoms• Diminished or absent reflexes• No other aetiology for flaccid weakness identified.

Hughes Scale[131]0 - healthy

1 - minor symptoms or signs of neuropathy but capable of manual work

2 - able to walk without support of a stick but incapable of manual work

3 - able to walk with a stick, appliance, or support

4 - confined to bed or chair-bound

5 - requiring assisted ventilation

6 - dead

Identification of patients with GBS at risk of respiratory failureusing the 20/30/40 rule[108]In patients with no bulbar dysfunction, or with mild bulbar dysfunction without aspiration risk, the 20/30/40rule should be used.

ICU monitoring and elective intubation should be considered if:[108]

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• Vital capacity <20 mL/kg (odds ratio 15.0)• Maximal inspiratory pressure worse than -30 cmH2O• Maximal expiratory pressure <40 cmH2O• Reduction of 30% in vital capacity, maximal inspiratory pressure, or maximal expiratory pressure.

[VIDEO: Tracheal intubation animated demonstration ]

[VIDEO: Bag-valve-mask ventilation animated demonstration ]






Guillain-Barre syndrome Treatment

Step-by-step treatment approachA multidisciplinary approach to the acute phase combining supportive and disease-modifying therapy(with plasma exchange or high-dose immunoglobulin [IVIG]) is required. The use of plasma exchange orimmunoglobulin depends on the institution or whether the patient has a contraindication to immunoglobulinsuch as IgA deficiency. Both have been shown to be equally efficacious. One Cochrane review suggestedthat IVIG given within 2 weeks of the onset was as efficacious as plasma exchange, and more likely to becompleted than plasma exchange.[40] Their combination is not supported.

Supportive therapy: respiratory managementRespiratory failure is common, and up to 30% of patients need ventilatory support or airway protection.Risk factors for progression to mechanical ventilation include rapid disease progression, bulbardysfunction, bilateral facial nerve weakness, and dysautonomia. Pulse oximetry and ABGs should not berelied on, as hypoxia or hypercarbia is a late sign and patients will decompensate very quickly. There isinsufficient evidence to recommend specific methods for monitoring respiratory function, but respiratorystatus should be monitored in all patients.[132] Bedside spirometry should be performed every 6 hoursinitially. Early spirometry will also help triage the patient between the ICU and regular ward. Patients withbulbar dysfunction, high risk of aspiration (i.e., infiltrates on CXR), and new atelectasis on CXR shouldbe intubated early for airway protection and impending respiratory failure. In patients with no bulbardysfunction or with mild bulbar dysfunction without aspiration risk, the 20/30/40 rule should be used asdetailed below.[108] The patient should be monitored in the ICU and elective intubation considered if:

• Vital capacity is <20 mL/kg• Maximal inspiratory pressure is worse than -30 cmH2O (negative inspiratory force)• Maximal expiratory pressure is <40 cmH2O• Vital capacity, maximal inspiratory pressure, or maximal expiratory pressure is reduced by 30%

from baseline initial measurement.[108]

The mean duration of ventilation is 15 to 43 days, and weaning should be guided by serial PFTsand assessment of strength.[132] The need for tracheostomy should be addressed from week 2onwards, especially if PFTs do not show improvement. If there is improvement of PFTs above baseline,tracheostomy may be delayed by an additional week before reassessment.[132]

[VIDEO: Tracheal intubation animated demonstration ]

[VIDEO: Bag-valve-mask ventilation animated demonstration ]

[VIDEO: Nasopharyngeal airway animated demonstration ]

[VIDEO: Oropharyngeal airway animated demonstration ]

Supportive therapy: cardiovascular managementHaemodynamic monitoring of pulse and BP should be started on admission. Telemetry would be prudenthere, especially if there is evidence of dysautonomia. If dysautonomia is present, continuous cardiacmonitoring and placement of a Foley catheter should be initiated on admission. There are insufficient datafor methods and setting of monitors, but all patients with severe disease should have their pulse and BPmonitored until they are off ventilator support and have begun to recover.[18] [132] Fluid balance shouldbe monitored carefully, especially because the autonomic dysfunction renders clinical determination of

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http://bestpractice.bmj.com/procedural-videos/en-gb/71bca003-7aea-4aa0-8ad9-aec5d654960c


Guillain-Barre syndrome TreatmentTR

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hydration status very difficult. Hypotensive episodes can be managed with fluid boluses. If BP is verylabile, then intra-arterial BP monitoring should be initiated. Hypertensive episodes should be treated withshort-acting agents (e.g., labetalol, esmolol, and nitroprusside) to prevent abrupt hypotension. Otherfactors that may potentiate dysautonomia include manoeuvres such as suctioning, changing position (i.e.,lying to sitting), and medicines (antihypertensive drugs, succinylcholine).[135]

Supportive therapy: DVT prophylaxisThere are no studies evaluating efficiency of DVT prophylaxis specifically in this disorder. Immobilityand hypercoagulability from treatments such as intravenous immunglobulin (IVIG) can increase therisk of DVT in these patients.[136] Subcutaneous heparin or enoxaparin and support stockings arerecommended for non-ambulatory patients until they are able to walk independently.[132]

Supportive therapy: pain managementGabapentin or carbamazepine are generally recommended in the ICU in the acute phase;[132] however,further studies are required to investigate the safety and efficacy of potential interventions in patientswith pain.[137] Adjuvant therapy with tricyclic antidepressants, tramadol, gabapentin, carbamazepine, ormexiletine may be helpful for long-term management of neuropathic pain.[132] Although opioids may beeffective, they may aggravate autonomic gut dysmotility and bladder distension.[82] [132] [138]

ImmunotherapyImmunotherapy comprises IVIG or plasma exchange. Both have been shown to be equallyefficacious.[139] The choice between them is often institution-dependent. IVIG is a pooled blood productand runs the risk of transmitting infection, and can precipitate anaphylaxis in an IgA-deficient person.It is, however, much easier to administer because it is a peripheral intravenous infusion. If there is acontraindication to IVIG, such as IgA deficiency or ongoing renal failure, then plasma exchange wouldbe a better option. Plasma exchange requires central venous access and close monitoring for electrolyteabnormalities and coagulopathies. When started within 2 weeks from symptom onset, IVIG has equivalentefficacy to exchange in hastening recovery in patients who require help with walking. Plasma exchangeis recommended for ambulatory patients beyond 2 weeks from onset of neurological symptoms, astrials with IVIG did not include ambulatory patients beyond 2 weeks of symptom onset.[140] [141]Complications are seen less frequently with IVIG than with plasma exchange, and hence IVIG may befavoured over plasma exchange.[142] There is no evidence concerning the relative efficacy of plasmaexchange and IVIG in axonal forms of GBS. Combination treatment (plasma exchange followed byIVIG) is not recommended.[40] [140] Unlike in other immune-mediated disorders, oral corticosteroidsare not beneficial and may even be harmful, possibly due to harmful effects on denervated muscle ordue to inhibition of the macrophage repair process.[143] Intravenous corticosteroids do not produce anysignificant short- or long-term benefits.[143]

Plasmapheresis (plasma exchange)Plasma exchange has been shown to be most effective if started within 7 days of symptom onset,but improvement in outcome was seen in a study despite giving initiating plasma exchange up to 30days after symptom onset.[38] [144] Plasma exchanges should be initiated in parallel with supportivecare. In mild GBS, 2 plasma exchanges are superior to 1 or none, and in moderate GBS, 4 plasmaexchanges are superior to 2.[38] In severe disease, where the patient is mechanically ventilated, 6 plasmaexchanges are not superior to 4.[38] The risk of relapse is higher with plasma exchange.[38] Large





randomised multicentre trials have established effectiveness in severe disease.[13] [145] [146] Evidencehas suggested that plasma exchange was superior to supportive care in the following areas:

• Mean time to recover walking with aid (primary outcome)• Shorter time to onset of recovery (primary outcome)• Improvement by 1 disability grade by 4 weeks (secondary outcome).

Other secondary outcomes include improvement in time to recover walking without aid, percentagerequiring mechanical ventilation, duration of ventilation, full muscle strength, recovery after 1 year, andsevere sequelae after 1 year.[38]

The recommended dose is given by central venous catheter, 50 mL/kg bodyweight over 7 to 14 daysstarted within 2 weeks of disease onset. Two plasma exchanges are given for mild GBS with disabilitygrade 0 to 2, and 4 plasma exchanges for severe GBS with disability grade 3 to 6 with albumin in thecontinuous flow machine.[38] It is recommended that plasma exchange be performed as early aspossible within 4 weeks of onset for non-ambulatory patients and within 2 weeks of onset for ambulatorypatients.[140]

Intravenous immunoglobulinThe goal of IVIG is to hasten recovery and reduce long-term morbidity. It is recommended for ambulatorypatients within 2 weeks from the onset of neurological symptoms.[40] [140] IVIG is recommended forpatients who require help to walk within 2 or 4 weeks from onset of neurological symptoms.[140]

Possible mechanisms for beneficial effects include blockade of Fc receptors on macrophages preventingantibody targeted attachment on Schwann cell membrane and myelin or on axolemma in axonal variantsof GBS; regulation of autoantibodies or cytokines by anti-idiotypic or anti-cytokine antibodies in the pooledimmunoglobulin; and interference with the complement cascade or regulatory effects on T cells.[147]

An alternative hypothesis may be that high concentrations of circulating immunoglobulin accelerate thebreakdown of IgG. Circulating IgG is picked up by a specialised receptor, FcRn, on the endothelial cellsurface, which endocytose the IgG and return it intact to the circulation. Excessive amounts of IgG exceedthe capacity of the recycling system, which diverts the excess to lysosomes, where it is broken down.[148]

RehabilitationThis is recommended in the acute phase. It comprises gentle strengthening involving isometric, isotonic,isokinetic, and manual resistive and progressive resistive exercises. It should be focused on properlimb positioning, posture, orthotics, and nutrition.[132] A multi-disciplinary approach has been shown toimprove disability and quality of life as well as reduce fatigue.[149]

Treatment details overviewConsult your local pharmaceutical database for comprehensive drug information including contraindications,drug interactions, and alternative dosing. ( see Disclaimer )

Acute ( summary )Patient group Tx line Treatment

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Acute ( summary )without IgA deficiency orrenal failure

1st plasma exchange

without IgA deficiency orrenal failure

plus supportive treatment


1st intravenous immunoglobulin (IVIG)



with IgA deficiency orrenal failure

1st plasma exchange







Treatment options

Acute

Patient group Tx line Treatment


1st plasma exchange

» Both plasma exchange and intravenousimmunoglobulin (IVIG) have been shown to beequally efficacious. The choice between them isoften institution-dependent.

» If there is a contraindication to IVIG (namely,IgA deficiency or ongoing renal failure), thenplasma exchange would be a better option.

» Ambulant patients: plasma exchange isrecommended within 2 weeks of onset. Twoplasma exchanges are given for mild GBS(disability grade 0 to 2).

» Non-ambulatory patients: plasma exchangeis recommended within 4 weeks from onset ofneurological symptoms.[140]

» Plasma is separated from cells usingmembrane filtration or centrifugationconcurrently with plasma and albuminreplacement. This is labour intensive andrequires teams skilled in extracorporealcirculation and exposes the patient to procedure-related morbidities.

» The dose for plasma exchange is giventhrough a central venous catheter (Mahurkar),50 mL/kg bodyweight every other day for 7 to 14days.[139] During administration, patients shouldbe closely monitored for electrolyte abnormalitiesand coagulopathies.

» Complications include severe infection, BPinstability, cardiac arrhythmias, and pulmonaryembolus.[150] [151] Compared with IVIG,plasma exchange showed more instancesof pneumonia, atelectasis, thrombosis, andhaemodynamic difficulties.[139] Other adverseeffects include hypocalcaemia.



» All patients with severe disease should havetheir pulse and BP monitored until they are offventilator support and have begun to recover.

» DVT prophylaxis: subcutaneous heparinor enoxaparin and support stockings are

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Acute

Patient group Tx line Treatmentrecommended for non-ambulatory patients untilthey are able to walk independently.[132]

» Intubation and ventilation: risk factors forrespiratory failure include rapid diseaseprogression, bulbar dysfunction, bilateral facialnerve weakness, and dysautonomia. Earlyintubation should be considered for patientswith bulbar dysfunction, high risk of aspiration,and new atelectasis on CXR. Elective intubationshould be considered in patients with no bulbar/mild bulbar dysfunction if vital capacity is<20 mL/kg; maximal inspiratory pressure isworse than -30 cmH2O; maximal expiratorypressure is <40 cmH2O; vital capacity, maximalinspiratory pressure, or maximal expiratorypressure is reduced by 30% from baselineinitial measurement.[108] Once the patient isintubated, the need for tracheostomy shouldbe addressed from week 2 onwards. If thereis no improvement of PFT, percutaneoustracheostomy should be performed. If thereis improvement of PFT above baseline,tracheostomy may be delayed for an additionalweek before reassessment.[132]

[VIDEO: Tracheal intubationanimated demonstration ]

[VIDEO: Bag-valve-mask ventilationanimated demonstration ]

» Pain in the acute phase: gabapentin orcarbamazepine are generally recommendedin the ICU;[132] however, further studies arerequired to investigate the safety and efficacy ofpotential interventions in patients with pain.[137]Tricyclic antidepressants, tramadol, gabapentin,carbamazepine, or mexiletine may be helpful forlong-term management of neuropathic pain.

» Rehabilitation: all patients should undergoan individual programme of rehabilitation in theacute phase.[132] A multi-disciplinary approachhas been shown to improve disability and qualityof life as well as reduce fatigue.[149]

» Hypotension: can be managed with fluidboluses. Intra-arterial BP monitoring should bestarted if BP is very labile.

» HTN: should be treated with short-actingagents to prevent overshoot phenomenon.Episodes of HTN can be treated with labetalol,esmolol, or nitroprusside.









Acute

Patient group Tx line Treatmentwithout IgA deficiency orrenal failure

1st intravenous immunoglobulin (IVIG)

» Both plasma exchange and IVIG have beenshown to be equally efficacious. The choicebetween them is often institution-dependent.IVIG is a pooled blood product and runs therisk of transmitting infection, and can precipitateanaphylaxis in an IgA-deficient person. It is,however, much easier to administer because it isa peripheral intravenous infusion.

» In ambulatory patients IVIG is recommendedwithin 2 weeks of symptom onset.[40] [140][141] In non-ambulatory patients IVIG isrecommended within 2 to 4 weeks of onset.[140]

» Complications have been found to besignificantly less frequent with IVIG than withplasma exchange.[140] Potential complicationsinclude transmission of infective agents (e.g.,HIV, hepatitis B or C, Creutzfeldt-Jakob disease)and anaphylaxis (almost always in patients withsevere immunoglobulin A deficiency).[40]

Primary options

» intravenous normal immunoglobulin human:400 mg/kg/day intravenously for 5 days




» DVT prophylaxis: subcutaneous heparinor enoxaparin and support stockings arerecommended for non-ambulatory patients untilthey are able to walk independently.[132]

» Intubation and ventilation: risk factors forrespiratory failure include rapid diseaseprogression, bulbar dysfunction, bilateral facialnerve weakness, and dysautonomia. Earlyintubation should be considered for patientswith bulbar dysfunction, high risk of aspiration,and new atelectasis on CXR. Elective intubationshould be considered in patients with no bulbar/mild bulbar dysfunction if vital capacity of<20 mL/kg; maximal inspiratory pressure isworse than -30 cmH2O; maximal expiratorypressure is <40 cmH2O; vital capacity, maximalinspiratory pressure, or maximal expiratorypressure is reduced by 30% from baselineinitial measurement.[108] Once the patient isintubated, the need for tracheostomy shouldbe addressed from week 2 onwards. If there

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Acute

Patient group Tx line Treatmentis no improvement of PFT, percutaneoustracheostomy should be performed. If thereis improvement of PFT above baseline,tracheostomy may be delayed for an additionalweek before reassessment.[132]

[VIDEO: Tracheal intubationanimated demonstration ]




» Hypotension: this can be managed with fluidboluses. Intra-arterial BP monitoring should bestarted if BP is very labile.



1st plasma exchange

» If there is a contraindication to intravenousimmunglobulin (namely, IgA deficiency orongoing renal failure), then plasma exchangewould be a better option.

» Ambulant patients: plasma exchange isrecommended within 2 weeks of onset. Twoplasma exchanges are given for mild GBS(disability grade 0 to 2).

» Non-ambulatory patients: plasma exchangeis recommended within 4 weeks from onset ofneurological symptoms.[140]

» Plasma is separated from cells usingmembrane filtration or centrifugationconcurrently with plasma and albumin









Acute

Patient group Tx line Treatmentreplacement. This is labour intensive andrequires teams skilled in extracorporealcirculation, and exposes the patient toprocedure-related morbidities.

» The dose for plasma exchange is giventhrough a central venous catheter (Mahurkar),50 mL/kg bodyweight every other day for 7-14days.[139] During administration, patients shouldbe closely monitored for electrolyte abnormalitiesand coagulopathies.

» Complications include severe infection, BPinstability, cardiac arrhythmias, and pulmonaryembolus.[150] [151] Compared with IVIG,plasma exchange showed more instancesof pneumonia, atelectasis, thrombosis, andhaemodynamic difficulties.[139] Other adverseeffects include hypocalcaemia.




» DVT prophylaxis: subcutaneous heparinor enoxaparin and support stockings arerecommended for non-ambulatory patients untilthey are able to walk independently.[132]

» Intubation and ventilation: risk factors forrespiratory failure include rapid diseaseprogression, bulbar dysfunction, bilateral facialnerve weakness, and dysautonomia. Earlyintubation should be considered for patientswith bulbar dysfunction, high risk of aspiration,and new atelectasis on CXR. Elective intubationshould be considered in patients with no bulbar/mild bulbar dysfunction if vital capacity of<20 mL/kg; maximal inspiratory pressure isworse than -30 cmH2O; maximal expiratorypressure is <40 cmH2O; vital capacity, maximalinspiratory pressure, or maximal expiratorypressure is reduced by 30% from baselineinitial measurement.[108] Once the patient isintubated, the need for tracheostomy shouldbe addressed from week 2 onwards. If thereis no improvement of PFT, percutaneoustracheostomy should be performed. If thereis improvement of PFT above baseline,tracheostomy may be delayed for an additionalweek before reassessment.[132]

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» Hypotension: this can be managed with fluidboluses. Intra-arterial BP monitoring should bestarted if BP is very labile.










EmergingComplement activation inhibitionDrugs inhibiting various stages of complement activation are being tried in several antibody-mediatedneurological diseases. This is likely also to be useful in GBS, especially with positive antigangliosideantibodies.

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RecommendationsMonitoringMost patients show continued progression for up to 2 weeks followed by a plateau phase of 2 to 4 weeksand recovery of function. Patient should have follow-up within 2 weeks after the acute syndrome toevaluate for relapse, at which point repeat intravenous immunoglobulin or plasma exchange can beconsidered. Thereafter, follow-up is every 4 to 6 weeks for 6 months, then to 6 months for 1 year, and thenyearly. Patient should continue working with physiotherapy and occupational therapy.

Patient instructionsPatients should be instructed to contact their physician with any worsening symptoms of weakness,numbness, paraesthesia, facial weakness, difficulty with swallowing or breathing, or worsening bladderfunction.

Complications

Complications Timeframe Likelihoodrespiratory failure short term medium

Neuromuscular respiratory function becomes compromised in 17% to 30% of patients with GBS. In somepatients, bulbar dysfunction causes difficulty with clearing secretions, compromising gas exchange andincreasing the risk of aspiration.

Clinical features that indicate fatigue of respiratory muscles are tachypnoea, sweating, tachycardia,asynchronous movements of the chest and abdomen, and episodic use of accessory muscles ofrespiration.[132]

In the case of worsening respiratory failure, patient should be started on invasive or non-invasivemechanical ventilator.

bladder areflexia short term medium

Bladder areflexia and disturbed bladder sensation occurs secondary to dysfunction of peripheral types ofparasympathetic and somatic nerve.[81]

Voiding is more frequently compromised with axonal type GBS. Micturitional disturbances on urodynamicstudies have shown evacuation and storage disorders, bladder areflexia, and disturbed bladder sensationindicative of peripheral types of parasympathetic and somatic nerve dysfunction.

Maintaining an indwelling Foley catheter during the acute phase is helpful.[132]

adynamic ileus short term medium




Guillain-Barre syndrome Follow up

Complications Timeframe LikelihoodAdynamic ileus occurs secondary to dysfunction of the autonomic nervous system. Daily abdominalexamination and auscultation should be performed to detect this early.[132]

Feeding should be suspended and nasogastric tube placed. Nasogastric feeds can be given at 10 mL/hourif the ileus is not severe.

Opioids should be avoided and promotility agents are contraindicated with dysautonomia.

Erythromycin or neostigmine may be helpful.[156] [157]

paralysis short term medium

After 1 year approximately 15% of patients are unable to walk without help.[1]

Treatment in the acute phase should include an individual programme of gentle strengthening involvingisometric, isotonic, isokinetic, and manual resistive and progressive resistive exercises.

Rehabilitation should be focused on proper limb positioning, posture, orthotics and nutrition.[132]

fatigue long term high

The cause and contributing factors are not fully known, but fatigue appears in part to be a sequel of forcedinactivity and general muscle deconditioning.

Supervised exercise programmes are recommended for both fatigue and functional abilities, which weremeasurably improved in studies.[132]

immobilisation hypercalcaemia long term low

This may become evident approximately 4 months after the onset of paralysis, as in other states ofimmobilisation that favour resorption of the calcium.[154] Subcutaneous calcitonin combined with oraletidronate disodium has been found to be useful if sodium infusions fail.[155]

DVT variable medium

Immobilisation is a risk factor for the development of DVT.[158] There is a lack of clinical studies thataddress methods of prophylaxis or monitoring of patients at risk for thrombosis. Observational studies inorthopaedic or general surgery patients suggest a benefit from subcutaneous heparin 5000 U every 12hours in preventing DVT.

In acutely ill medical patients, prophylactic treatment with subcutaneous enoxaparin 40 mg daily reducedthe incidence of DVT from 15% to 5% compared with placebo. Support stockings reduced the risk byalmost 70% in patients at moderate risk for DVT post-operatively.

Subcutaneous heparin or enoxaparin and support stockings are recommended for non-ambulatory adultpatients.[132]

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Prognosis

The overall prognosis of GBS is good, with approximately 85% of survivors making a good functionalrecovery. Mortality of 20% has been shown in ventilated patients.[152]

Prognosis worsens with older age.[24] [58] Factors associated with poorer outcome include more severeweakness, rapid onset, older age, muscle wasting, electrically inexcitable nerves, and preceding diarrhoealillness.[1] Miller-Fisher syndrome has a better prognosis than other GBS subtypes. Most severely disabledpatients with acute motor axonal neuropathy have been found to walk independently within a few years.[2]Most patients with a poor outcome have been mechanically ventilated. Mortality of 20% has beendemonstrated in these patients.[152] Recovery from severe disease may be prolonged, but most patientsare able to walk independently.[152] Acute and long-term disability appear to be associated with axonalinvolvement and a Hughes score ≥2 at the lowest point.[153]




Guillain-Barre syndrome Guidelines

Diagnostic guidelines

Europe

Diagnostic and classification criteria for the Guillain-Barre syndromePublished by: GBS-consensus group of the Dutch NeuromuscularResearch Support Centre

Last published: 2001

Summary: Discusses the diagnostic criteria for clinical diagnosis.

Electrophysiological classification of Guillain-Barre syndromePublished by: Plasma Exchange/Sandoglobulin Guillain-BarreSyndrome Trial Group

Last published: 1998

Summary: Discusses neurophysiological criteria for acute inflammatory demyelinatingpolyradiculoneuropathy (AIDP), acute motor-sensory axonal neuropathy (AMSAN), and acute motor axonalneuropathy (AMAN).

Treatment guidelines

North America

Practice parameter: immunotherapy for Guillain-Barre syndromePublished by: American Academy of Neurology Last published: 2003Summary: Provides an evidence-based statement to guide immunotherapy use. Plasma exchange isrecommended for non-ambulatory patients within 4 weeks of onset and for ambulatory patients within2 weeks of onset. Intravenous immunglobulin (IVIG) is recommended within 2 to 4 weeks from onsetfor patients requiring help to walk. Combination treatment with plasma exchange followed by IVIG is notrecommended.

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Guillain-Barre syndrome ReferencesR

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• Hadden RD, Hughes RA. Management of inflammatory neuropathies. J Neurol Neurosurg Psychiatry.2003;74(suppl 2):ii9-ii14. Full text Abstract

• Hahn AF. Guillain-Barré syndrome. Lancet. 1998;352:635-641. Abstract

• Stowe J, Andrews N, Wise L, et al. Investigation of the temporal association of Guillain-Barrésyndrome with influenza vaccine and influenzalike illness using the United Kingdom General PracticeResearch Database. Am J Epidemiol. 2009;169:382-388. Full text Abstract

• Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome.Cochrane Database Syst Rev. 2014;(9):CD002063. Full text Abstract

• Lawn ND, Fletcher DD, Henderson RD, et al. Anticipating mechanical ventilation in Guillain-Barrésyndrome. Arch Neurol. 2001;58:893-898. Full text Abstract

• Hughes RA, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database SystRev. 2012;(8):CD001446. Full text Abstract

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Contributors:

// Authors:

Saiju Jacob, MD, DPhil, MRCP (UK), FRCP (Lon)Consultant NeurologistQueen Elizabeth Neurosciences Centre, University Hospital Birmingham, Birmingham, UKDISCLOSURES: SJ declares that he has no competing interests.

// Acknowledgements:Dr Saiju Jacob would like to gratefully acknowledge Dr John B. Winer, Dr Michael T. Torbey, Dr DhruvilJ. Pandya, and Dr Prem A. Kandiah, previous contributors to this monograph. JBW, MTT, DJP, and PAKdeclare that they have no competing interests.

// Peer Reviewers:

Cigdem Akman, MDDivision of Pediatric NeurologyColumbia University College of Physicians and Surgeons, New York, NYDISCLOSURES: CA declares that he has no competing interests.

Robert Hadden, FRCP, PhDConsultant NeurologistKing's College Hospital, London, UKDISCLOSURES: RH has been paid by Baxter Heathcare Ltd for membership of its neurology advisoryboard, and is a co-author of several studies referenced in this monograph.

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