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Clinical Medicine 2010, Vol 10, No 4: 399–401CME Neurology

Jane Pritchard, consultant neurologist,Neuromuscular Unit, 3 North, ImperialCollege Healthcare NHS Trust, CharingCross Hospital, London

Guillain-Barré syndrome (GBS), with anannual incidence of 1–2 per 100,000, isthe most common cause of neuromus-cular paralysis in the western world. Evenwith modern intensive care and intra-venous (iv) immunoglobulin (Ig) treat-ment there remains an associatedmortality rate between 3.5% and 12% inthe acute phase1 and residual disabilityrate of 20% or more. Many other patientsare left with long-term fatigue.

History and examinationfindings

GBS can be difficult to diagnose early asit can present with vague symptoms ofweakness, neck or back pain and paraes-thesia. It can also be difficult in atypicalcases, with unusual distribution of weak-ness, for example presenting in the upperlimbs or focusing on respiratory muscleswith relative preservation of limbstrength. An initial discharge from casu-alty is not uncommon, but patients withsuspected GBS should be admitted andcarefully observed in case paralysisand/or life-threatening bulbar dysfunc-tion evolve rapidly.

There is little diagnostic doubt once itevolves into the classical picture of sym-metrical quadriplegia, possibly also withrespiratory muscle, facial and bulbarweakness. Weakness can appear ‘pyra-midal’ in distribution, with hip and kneeflexor weakness without other features of‘upper motor neurone’ pathology. Totalareflexia may evolve over a few days frominitial hyporeflexia. By definition, theevolution of progression of weakness oftwo or more limbs from normality tonadir should be less than four weeks2 andusually two weeks or less. A smallminority have subacute symptom pro-

gression over 4–8 eight weeks, but anylonger would suggest an alternative diag-nosis. Very occasional patients appear tohave a relapsing variant of GBS. Sensorysymptoms and signs are usually mild.Other variants include the Miller-Fishersyndrome (MFS), originally described asataxia, ophthalmoplegia and areflexia,but also including patients with morewidespread cranial nerve involvement.MFS features can overlap with GBS.

GBS does not usually cause visualfailure, hearing loss or early sphincterinvolvement. There should not be feverdue to GBS nor a sharp sensory level.

Approximately two-thirds of patientsreport antecedent infection (eg diar-rhoea, classically due to Campylobacterjejuni3 or upper respiratory tract infec-tion) in the previous six weeks.Anecdotal reports have reported GBSafter vaccination, but only the USA 1976swine flu vaccination programme hasbeen causally linked to GBS.4

Aetiology

GBS is believed to be due to an autoim-mune attack on peripheral nerves, occur-ring in previously healthy patientswithout evidence of other autoimmunediseases. Some of the antecedent infec-tions most commonly associated withGBS (eg C. jejuni) are known to sharestructural similarities with componentsof peripheral nerves. Post-mortemstudies and nerve biopsies show antibodyand complement deposition, T cell and

macrophage infiltration of nerves.Multiple immunological derangementshave been described in the acute phase ofGBS, the most robust of which are anti-bodies directed against individual orcombinations of gangliosides.

Differential diagnosis (Table 1)

The differential diagnosis is relatively wideearly in the syndrome, the initial focusbeing on locating the pathology in thenerve roots and peripheral nerves ratherthan elsewhere in the nervous system.When a diagnosis of a neuropathy has beenmade, the differential diagnosis includes:

• infection (lyme, diphtheria)

• inflammatory (neurosarcoid)

• paraneoplastic

• malignant (due to infiltration of nerveroots)

• vasculitic

• metabolic (beri-beri due to vitaminB1 deficiency)

• postinfectious/autoimmune in origin(GBS).

Confirmatory tests

GBS is a clinical diagnosis arrived at fol-lowing exclusion of other mimics andwith supportive tests.5

Neurophysiology is helpful – initialabnormalities are found in 85% of cases –but may be subtle (eg prolonged ‘f ’ wavelatencies, dispersed motor potentials andprolonged distal motor latencies).6

Neurophysiology helps to subclassify

Guillain-Barré

syndrome

Brainstem lesion StrokeEncephalitis

Spinal cord Polio virusJapanese encephalitisEnterovirus 71West Nile virusInflammatory, infectious, compressive cord

or cauda equina lesions

Neuromuscular junction Myasthenia gravisBotulism

Muscle MetabolicLow K/PO4InflammatoryInfectious

Table 1. Differential diagnosis of anatomical site of cause of progressive paralysis,with underling possible aetiologies.

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disease as predominantly demyelinating oraxonal.Axonal variants are relatively rare inthe UK, whereas they dominate in Chinaafter seasonal outbreaks of C. jejuni.7

A lumbar puncture should be done beforetreatment. A cerebrospinal fluid (CSF)white cell count of over 10/�l raises thepossibility of leptomeningeal malignancy,HIV or an alternative infectious diagnosis(eg Lyme disease or poliomyelitis), but inclinical trials CSF cell counts up to 50/�l arepermitted. IvIg can very occasionally causean aseptic meningitis. Typically, the CSFprotein is raised after the first week, often tomore than 1 g/l.

Routine blood tests should include crea-tine kinase, biochemistry and Ig levels.These are done to exclude other causes ofweakness and to reduce the risks of ivIg. Inrenal failure ivIg is relatively contraindi-cated and it is more likely to cause anaphy-laxis in patients with IgA deficiency.

Antiganglioside antibodies are usuallytested in GBS but their absence does notexclude the diagnosis. Increasing evi-dence suggests that they are pathogenic.8

Gangliosides are widespread in the ner-vous system as they help maintain cellmembrane structure:

• 25% of patients with the acuteinflammatory demyelinating (AIDP)GBS variant possess antiganglioside(usually GM1) antibodies

• 95% of patients with Miller-Fishersyndrome possess anti-GQ1b anti-bodies

• 50% of patients with axonal variants(acute motor axonal neuropathy)possess anti-GM1 antibodies.

Life-saving measures (Table 2)

Cardiac arrhythmias and declining respi-ratory function can be life-threatening. Acardiac monitor and regular vitalcapacity (VC) measurements are essen-tial, at least until the patient is mobile.The frequency of VC monitoring (eghourly to qds) should be tailoredaccording to the clinical state. Peak expi-ratory flow rates are no substitute.Intensive care should be alerted early ifthere is any clear bulbar involvement,and elective intubation instituted as VCapproaches 15 ml/kg.9 Declining oxygen

saturations and changes in arterial bloodgas values may mean that respiratoryarrest is imminent. Prevention of deepvein thrombosis is paramount withthromboembolic disease stockings andsubcutaneous heparin.

Treatment

Randomised controlled trials show thatthe recovery of non-ambulant patientstreated within two weeks of symptomonset is hastened by 0.4 g/kg/day ivIg forfive days or 4–6 plasma exchanges.10,11

Plasma exchange can help ambulantpatients and those with symptoms of upto 30 days. By extrapolation, a similarbenefit might be inferred from ivIg, buttrials have not been conducted in thesepatient groups.

Treatment should be started as soon aspossible, but there is no evidence thatstarting it 12 hours earlier (egovernight) makes any difference. First-line treatment is now usually ivIgbecause of its ease of administration.Some patients respond initially to ivIgbut the effect wears off within six weeks.Anecdotal evidence supports the use offurther ivIg in these ‘treatment-relatedfluctuations’ (reviewed in Ref 12). Forthose patients not responding to treat-ment there is no evidence that giving asecond course of ivIg is of any benefit.This is now being tested in a trial (per-sonal communication; InflammatoryNeuropathy Consortium).

There is no evidence that steroids help,although they do not hinder so should begiven if needed for other reasons,13 orthat giving plasma exchange followed byivIg is better than plasma exchange alone.

Rehabilitation

Adequate pain relief and a multidiscipli-nary approach to rehabilitation areessential, as is patient education duringthe slow but steady recovery, withimprovements to be expected for up totwo years. The GBS Support Group has auseful website (www.gbs.org.uk) andsupport phone line. The US equivalent isthe GBS Foundation International(www.gbs-cidp.org).

• Vital capacity hourly

• CXR

• Oxygen saturations/ABG as baseline

• Cardiac monitoring

• Swallow assessment

• TED stockings

• Bloods to include CK, ESR,biochemistry, Ig

ABG � arterial blood gas; CK � creatinekinase; CXR � chest X-ray; ESR � erythrocytesedimentation rate; Ig � immunoglobulin; TED � thromboembolic deterrant.

Table 2. Suggested emergency/acutemedical unit management steps.

Guillain-Barré syndrome (GBS) is a clinical diagnosis, with progressive weaknessand areflexia evolving over less than four weeks

Antiganglioside antibodies are present in 25% of patients with typical acutedemyelinating GBS; in Miller-Fisher syndrome 95% of patients possessantibodies against GQ1b ganglioside

More than 10 white cells in cerebrospinal fluid should raise concern of alternativediagnoses including HIV

Emergency management must include vital capacity and cardiac monitoring, togetherwith early intubation for patients with declining respiratory and bulbar function

Standard treatment is intravenous immunoglobulin 0.4 g/kg/day for five days in non-ambulant patients

Key Points

KEY WORDS: Guillain-Barré syndrome, immunoglobulin, neuropathy, paralysis

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News

GBS is receiving more media coveragedue to anxiety about whether the currentswine flu outbreak will lead to morecases. All cases of GBS either in isolation,or linked to swine flu or the swine fluvaccine should be notified to the BritishNeurological Surveillance Unit. Recentanalysis of historical data suggests, atleast for seasonal influenza, that the virusitself is far more likely than its vaccine tolead to GBS.14 Individuals are advised totalk to their general practitioner andneurologist or consult the advice pages ofthe GBS Support Group for generaladvice about vaccine use after GBS.

The future

Much remains to be done to reduce theburden of disability after GBS. Earlydetermination of potential non- or poorresponders to current treatment mightalter their management. Recent worksuggests that patients exhibit varyingpharmacokinetics of ivIg metabolismand thus might require different orrepeated doses of ivIg.15 Better under-standing of the pathogenesis and targetantigen for the immune response in theusual AIDP GBS variant will be critical.The treatment of a monophasic autoim-mune disease such as GBS is hamperedby the limited ability to switch off aprocess already well underway beforesigns develop.

Biological treatments currently underinvestigation include monoclonal anti-bodies directed against components of

the complement pathway; these preventantiganglioside antibody-induced neu-ropathy in murine models.16 Trials ofnovel treatments are likely to be hin-dered to some degree by the need to addthem to ivIg as the current gold stan-dard, and paradoxically by the now swifttreatment of patients in district generalhospitals where it will be more difficultto recruit an occasional patient to atreatment trial in GBS compared withthe days of the large ivIg and plasmaexchange trials.

References

1 Hughes RA, Cornblath DR. Guillain-Barrésyndrome. Lancet 2005;366:1653–66.

2 Asbury AK, Cornblath DR. Assessment ofcurrent diagnostic criteria for Guillain-Barré syndrome. Ann Neurol1990;27(Suppl):S21–4.

3 Rees JH, Soudain SE, Gregson NA, HughesRA. Campylobacter jejuni infection andGuillain-Barré syndrome. N Engl J Med1995;333:1374–9.

4 Langmuir AD, Bregman DJ, Kurland LT,Nathanson N, Victor M. An epidemiologicand clinical evaluation of Guillain-Barrésyndrome reported in association with theadministration of swine influenza vaccines.Am J Epidemiol 1984;119:841–79.

5 Pritchard J. What’s new in Guillain-Barrésyndrome? Pract Neurol 2006;6:208–17.

6 Hadden RD, Cornblath DR, Hughes RA et al. Electrophysiological classification of Guillain-Barré Syndrome: clinical associations and outcome. PlasmaExchange/Sandoglobulin Guillain-BarréSyndrome Trial Group. Ann Neurol1998;44:780–8.

7 McKhann GM, Cornblath DR, Ho T et al.Clinical and electrophysiological aspects ofacute paralytic disease of children and

young adults in northern China. Lancet1991;338:593–7.

8 Willison HJ, Yuki N. Peripheral neuropathiesand anti-glycolipid antibodies. Brain2002;125:2591–625.

9 Mehta S. Neuromuscular disease causingacute respiratory failure. Respir Care2006;51:1016–21.

10 Hughes RA, Raphaël JC, Swan AV, vanDoorn PA. Intravenous immunoglobulinfor Guillain-Barré syndrome. CochraneDatabase Syst Rev 2006;(1):CD002063.

11 Raphaël JC, Chevret S, Hughes RA, AnnaneD. Plasma exchange for Guillain-Barré syndrome (update). Cochrane Database Syst Rev 2002;(2):CD001798.

12 Winer JB. What to do – when the Guillain-Barre patient fails to respond to treatment.Pract Neurol 2009;9:227–30.

13 Hughes RA, Swan AV, Van Koningsveld R,van Doorn PA. Corticosteroids forGuillain-Barré syndrome. CochraneDatabase Syst Rev 2006;(2):CD001446.

14 Kuitwaard K, de Gelder J, Tio-Gillen AP et al. Pharmacokinetics of intravenousimmunoglobulin and outcome in Guillain-Barré syndrome. Ann Neurol2009;66:597–603.

15 Stowe J, Andrews N, Wise L, Miller E.Investigation of the temporal association of Guillain-Barre syndrome with influenzavaccine and influenza like illness using theUnited Kingdom General Practice ResearchDatabase. Am J Epidemiol 2009;169:382–8.

16 Halstead SK, Zitman FM, Humphreys PDet al. Eculizumab prevents anti-gangliosideantibody-mediated neuropathy in a murinemodel. Brain 2008;131(Pt 5):1197–208.

Address for correspondence:

Dr J Pritchard, Neuromuscular Unit,

3 North, Imperial College Healthcare

NHS Trust, Charing Cross Hospital,

Fulham Palace Road, London W6 8RF.

Email: jane.pritchard@imperial.nhs.uk

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