mimics and chameleons in guillain-barre and miller fisher syndromes

Mimics and chameleons in Guillain–Barré and Miller Fisher syndromes

Benjamin R Wakerley,1 Nobuhiro Yuki2

1Department of Neurology,Gloucestershire Royal Hospital,Gloucester, UK2Departments of Medicine andPhysiology, Yon Loo Lin Schoolof Medicine, National Universityof Singapore, Singapore

Correspondence toBenjamin Wakerley, Departmentof Neurology, GloucestershireRoyal Hospital, GloucesterGL1 3NN, UK;[email protected]

Accepted 25 August 2014

To cite: Wakerley BR, Yuki N.Pract Neurol Published OnlineFirst: [please include DayMonth Year] doi:10.1136/practneurol-2014-000937

ABSTRACTGuillain–Barré syndrome (GBS) and its variant,Miller Fisher syndrome (MFS) have severalsubtypes, together forming a continuous spectrumof discrete and overlapping syndromes. Such is theheterogeneity within this spectrum that manyphysicians may be surprised to learn that thesedisorders are related pathophysiologically, andtherefore share certain clinical features. Theseinclude history of antecedent infection,monophasic disease course and symmetricalcranial or limb weakness. The presence ofcerebrospinal fluid albuminocytologicaldissociation (raised protein, normal cell count),antiganglioside antibodies and neurophysiologicalevidence of axonal or demyelinating neuropathyalso support a diagnosis in many cases, but shouldnot be relied upon. Mimics of GBS and MFS canbroadly be divided into those presenting withsymmetrical limb weakness and those presentingwith brainstem signs. MFS and the pharyngeal-cervical-brachial variant of GBS are frequentlymistaken for brainstem stroke, botulism ormyasthenia gravis, whereas Bickerstaff’s brainstemencephalitis is often diagnosed as Wernicke’sencephalopathy. Chameleons or atypicalpresentations of GBS-related disorders include:paraparetic GBS, bifacial weakness withparaesthesias, acute ataxic neuropathy, acuteophthalmoparesis, acute ptosis and acutemydriasis. Many neurologists may also not beaware that deep tendon reflexes remain present ormay even appear brisk in up to 10% of patientswith GBS. Correct diagnosis of GBS-relateddisorders helps to avoid unnecessary investigationsand allows early immunotherapy if appropriate.

INTRODUCTIONGuillain–Barré syndrome (GBS) is anumbrella term describing a heterogeneousgroup of related disorders, includingMiller Fisher syndrome (MFS) and GBSsubtypes (box 1).1 The common patho-genesis of these disorders is mirrored byseveral shared clinical features, including:history of antecedent infection, mono-phasic disease course and symmetrical

cranial or limb weakness. Many neurolo-gists believe that GBS only affects the per-ipheral nerves, but this is not always thecase, as 10% of patients display normalor even brisk deep tendon reflexes duringthe disease course.2 3 The clinical presen-tation of GBS-related disorders is hetero-geneous and the diagnosis may not beobvious at first. Here, we review themost important differential diagnoses(Mimics) for patients presenting withacute flaccid paralysis and brainstem syn-dromes and highlight some of the moreunusual presentations (Chameleons) ofGBS-related disorders.

THE GBS SPECTRUMGBS has one principal variant, known asMFS. Five per cent of patients with MFSdevelop weakness during disease course,indicating that MFS and GBS form a con-tinuum.4 GBS and MFS have been sub-classified into several subtypes, whichtogether form a continuous spectrum ofdiscrete and overlapping syndromes,affecting the cranial nerves and the limbs(figure 1). Although neurophysiologically,GBS-related disorders can be divided intoaxonal and demyelinating types; a classi-fication based on clinical criteria is moreuseful.1

Patients with ‘classic’ GBS develop tet-raparesis, although there are three loca-lised subtypes. These include: thepharyngeal-cervical-brachial variant ofGBS,5 causing bulbar, cervical and upperlimb weakness; paraparetic GBS,6–8

causing bilateral lower limb weakness;and bifacial weakness with paraesthesias,9

causing bilateral facial weakness anddistal limb sensory disturbance.MFS is characterised by ophthalmople-

gia, cerebellar-like ataxia and areflexia10

in the absence of limb weakness. Patientswith additional involvement of the reticu-lar formation, resulting in disturbance ofconsciousness, are said to have the

REVIEW

Wakerley BR, et al. Pract Neurol 2014;0:1–10. doi:10.1136/practneurol-2014-000937 1

http://pn.bmj.com

central nervous system (CNS) subtype, known asBickerstaff ’s brainstem encephalitis.11 There are alsoseveral incomplete forms of MFS, defined upon thepresence or absence of ophthalmoplegia or ataxia.There is also overlap between the variants.For example, patients with ophthalmoplegia, ataxiaand limb weakness are said to have MFS overlappedwith GBS.

CLINICAL FEATURESHistoryA careful history indicates that there are antecedentupper respiratory or gastrointestinal infective

symptoms in over 90% of patients who developGBS.12 Campylobacter jejuni, the most commoncause of acute bacterial gastroenteritis, is consistentlyidentified as the most frequent antecedent infection,occurring in up to 30% of patients.13 However, onlyone in 1000 patients with C. jejuni infection developGBS.14 The median time interval between onset ofdiarrhoea and development of neurological symptomsis 10 days, but may be as short as 3 days or as long as6 weeks.15 Several other bacterial and viral infectionsare associated with the development of GBS.16 Theseinclude: Haemophilus influenzae, Mycoplasmapneumoniae, cytomegalovirus, Epstein–Barr virus andvaricella zoster virus. Some of the remaining patientswith no antecedent infectious symptoms may still beharbouring asymptomatic infection. For example, halfthe patients with C. jejuni do not develop gastrointes-tinal symptoms.There are also non-infective associations reported.16

These include parenteral gangliosides for treating per-ipheral neuropathy and various vaccines (eg, H1N1influenza vaccine), which have the potential to inducemolecular mimicry. Other associations include auto-immune diseases (eg, systemic lupus erythematosus),immunosuppressive drugs (eg, anti-TNFα therapy)and surgery, probably reflecting the increased suscepti-bility to known infective triggers, some of which areasymptomatic.In most GBS and MFS subtypes, the onset of neuro-

logical symptoms is often with distal paraesthesiarather than weakness. This pattern also supports thepresence of polyneuropathy. In our experience, manypatients with GBS also report back pain, probablyrelating to inflammation of nerve roots.

Box 1 Guillain–Barré and Miller Fisher syndromesand their subtypes

Guillain–Barré syndrome▸ Paraparetic variant*▸ Pharyngeal–cervical–brachial weakness*

– Acute pharyngeal weakness*†▸ Bifacial weakness with paraesthesias*Miller Fisher syndrome▸ Acute ataxic neuropathy†▸ Acute ophthalmoparesis†▸ Acute ptosis†▸ Acute mydriasis†▸ Bickerstaff’s brainstem encephalitis‡

– Acute ataxic hypersomnolence‡†*Localised forms.†Incomplete forms.‡Central nervous system form.

Figure 1 Patterns of weakness in Guillain-Barré syndrome (GBS) and Miller Fisher syndrome and their subtypes. GBS and MillerFisher syndrome and their subtypes form a continuum of discrete and overlapping syndromes. Shaded areas indicate patterns ofweakness. The double outline (blurring the figures) indicates the presence of ataxia. ‘Zzzzz’ indicates hypersomnolence. The patternof weakness for each subtype are as follows: Classic GBS: tetraparesis with or without motor cranial nerve involvement; ParapareticGBS: lower limbs; Pharyngeal–cervical–brachial weakness: bulbar, neck and upper limbs; Bifacial weakness with paraesthesias: facial;Miller Fisher syndrome: external ophthalmoplegia; Bickerstaff’s brainstem encephalitis: external ophthalmoplegia. Facial weakness andmotor cranial nerve involvement are more frequent in demyelinating-type classic GBS (acute inflammatory demyelinatingpolyradiculoneuropathy) than in axonal-type (acute motor axonal neuropathy). In Miller Fisher syndrome, there is ataxia and in itscentral nervous system subtype, Bickerstaff’s brainstem encephalitis, there is additional hypersomnolence.

REVIEW

2 Wakerley BR, et al. Pract Neurol 2014;0:1–10. doi:10.1136/practneurol-2014-000937

ExaminationThere is a new diagnostic framework for GBS, MFSand their subtypes, which is likely to aid early diagno-sis and classification in the future.1 The key examin-ation finding in patients with GBS-related disorders isrelatively symmetric weakness, although some patientsdo develop asymmetric and rarely unilateral weakness.What follows next is a brief overview.Classic GBS (tetraparesis) can be diagnosed in

patients presenting with bilateral flaccid limb weak-ness, and is highly likely when there is also facialweakness.17 Distal limb numbness, paraesthesias orpain, may be the initial presenting symptom.Weakness is often ascending and may involve respira-tory muscles and cranial nerves. Up to 10% ofpatients have normal or exaggerated reflexes.2 3

MFS can be diagnosed in patients with ophthalmo-plegia, ataxia and areflexia.10 Patients with isolatedMFS have no limb weakness. Patients with additionalhypersomnolence have Bickerstaff ’s brainstem enceph-alitis.11 There are also incomplete forms of MFS inwhich ophthalmoplegia or ataxia is absent.18–21

There may also be overlap between subtypes.1

Patients with MFS or Bickerstaff ’s brainstem enceph-alitis who develop limb weakness can be diagnosed ashaving overlap with GBS. Patients with prominentophthalmoplegia or ataxia must have overlap withMFS. For example, patients presenting withpharyngeal-cervical-brachial weakness and ataxia haveoverlap with the pharyngeal-cervical-brachial variantof GBS, MFS or one of its subtypes.

Time course and progressionA core clinical feature of all GBS subtypes is the char-acteristic disease time course. In 90% of patients, thisis monophasic, although up to 10% of patientsdevelop recurrent or relapsing GBS.22 The time inter-val between onset of neurological symptoms andnadir ranges between 12 h and 28 days and is usuallyfollowed by subsequent clinical plateau or improve-ment.23 Treatment-related clinical fluctuations mayoccur within 8 weeks after starting immunotherapyand are regarded as part of a monophasic course.Patients who deteriorate after 8 weeks from initialonset or deteriorate three times or more despiteappropriate immunotherapy should be diagnosed withacute-onset chronic inflammatory demyelinating poly-radiculoneuropathy rather than GBS.24 Despite appro-priate immunotherapy, the overall mortality inpatients with GBS is 9% and 17% are left with severedisability.25 The prognosis in MFS is usually good.

InvestigationsThe most important early investigation is neuroima-ging to exclude an inflammatory, ischaemic or struc-tural cause for weakness, if felt clinically indicated. Inthe case of GBS, MR scans of brain and spinal cordshould be normal, although there may be gadolinium

enhancement of proximal nerve roots. In MFS andthe pharyngeal-cervical-brachial variant of GBS, MRscan of the brain helps to exclude brainstem path-ology, including restricted diffusion caused by acutestroke. Gadolinium contrast helps to exclude menin-geal pathology, especially at the skull base. Abnormalsignal change on T2-weighted MRI occurs in 11% ofpatients with Bickerstaff ’s brainstem encephalitis andmay involve the upper mesencephalon, thalamus,cerebellum or brainstem.26 Typically, cerebrospinalfluid (CSF) shows albuminocytological dissociation(high protein, normal cell count). In one large series,CSF protein was raised in 49% of patients on day 1and 88% after 2 weeks. Fifteen per cent had a mildpleocytosis (5–50 cells/mL (≤5)) but no one had morethan 50 cells/mL.3 Although nerve conduction studiesshould be performed early in suspected GBS, they areoften non-diagnostic in the first week and should notbe relied upon, or delay treatment, if there is a highindex of suspicion for GBS. Repeat CSF and nerveconduction studies after the first week are thereforeinvaluable if there is any doubt over the diagnosis.Serum antiganglioside antibody testing can help tosupport the diagnosis,27 but many centres test onlyfor anti-GM1 and anti-GQ1b antibodies, and theresults are often delayed.

NEUROLOGICAL CONDITIONS WHICH MIMIC GBS,MFS AND THEIR SUBTYPESGBS, MFS and their subtypes have numerous mimics,which can make diagnosis difficult, especially in earlydisease. In this review, we highlight the most import-ant differential diagnoses based on anatomical distri-bution of weakness, although there is significantoverlap. For example, botulism may mimic MFS orpharyngeal-cervical-brachial weakness in early diseasebut GBS in more established disease.

Acute flaccid paralysis mimicking GBSAlthough GBS is the most common cause of acuteflaccid paralysis, the differential diagnosis is broad(box 2) and may involve any part of the motor systembelow and including the spinal cord. A detailedhistory provides clues to aetiology and should include:recent travel, antecedent infective symptoms (eg,upper respiratory tract), vaccinations, insect or animalbites (eg, tick or snake bites), exposure to toxins (eg,organophosphates), drugs or contaminated food (eg,pickled sausages in the case of botulism) or water, sys-temic symptoms (eg, fever, rash), trauma (eg, neckinjury), family history (eg, familial hypokalaemic peri-odic paralysis) and psychiatric symptoms. By defin-ition, patients presenting with acute flaccid paralysisdo not show signs associated with CNS weakness (ie,increased muscle tone, hyper-reflexia, clonus andextensor plantar responses), but it is important tolook for other features of central involvement includ-ing: cerebellar ataxia, change in behaviour or

REVIEW


cognition and sphincter disturbance. Meningism,myalgia and autonomic instability also narrow thedifferential.Here, we consider viruses targeting anterior horn

cells and motor neurones, acute transverse myelitis,spinal cord injuries, acute peripheral neuropathies,neuromuscular weakness due to critical illness, disor-ders of the neuromuscular junction and disorders ofmuscle.28

Viruses targeting anterior horn cells or motor neuronsCertain viruses targeting anterior horn cells andmotor neurones may cause acute flaccid paraparesis.29

Extensive necrotising myelopathy on MRI is asso-ciated with herpes simplex virus and West Nile virus.Poliomyelitis should be considered in unvaccinatedindividuals, especially those with recent travel toendemic regions.30 Most patients infected with polioremain asymptomatic, but 0.1%–1.0% develops par-alysis. Typically, there is a prodromal flu-like illness,with fever, neck stiffness and significant myalgia.

Rapidly progressive, often asymmetric paralysis,affecting proximal more than distal muscles, developswithin 48 h in the absence of sensory deficit. CSFexamination is usually lymphocytic.Non-polio enterovirus, especially enterovirus 71,

may cause acute flaccid paraparesis and there havebeen recent outbreaks in Australia and Cambodia.31

Typically, a 1–2 week prodromal illness of diarrhoea,lethargy, irritability and nuchal rigidity is followed byacute flaccid paraparesis and other neurological symp-toms in up to 20% of individuals. The mortality ishigh.Rabies virus may cause acute flaccid paraparesis

1–2 months after initial exposure.32 Early symptomsinclude behavioural changes and autonomic instabil-ity, followed by ascending paralysis associated withsphincter involvement and sensory disturbance.Direct involvement of the spinal cord, nerve roots

and peripheral nerves may occur in HIV or AIDS, butmore often acute flaccid paraparesis is caused by theeffects of opportunistic infections. These include cyto-megalovirus, Epstein–Barr virus, varicella zoster virusand herpes simplex virus, which may also triggeracute motor axonal neuropathy.16 Cytomegalovirusand, less commonly, herpes simplex virus 2 or vari-cella zoster virus also cause polyradiculoneuropathy,especially if the patient is immunocompromised.Typically, there is ascending leg weakness, perinealparaesthesia, leg pain and variable bladder involve-ment. CSF usually shows increased polymorphs andprotein with reduced glucose. Neurophysiologically,there is evidence of axonal neuropathy. Cliniciansshould also consider other infections, including syph-ilis, toxoplasmosis, giardiasis and tuberculosis.29

Patients with AIDS with cachexia may develop rapidlyprogressive weakness due to profound B12 deficiency.

Acute transverse myelitisAcute transverse myelitis may cause acute flaccid para-paresis, usually with radiological evidence of spinalcord involvement. Initial spinal shock is followed byacute flaccid paraparesis associated with bladder dis-turbance and a sensory level. Often patients presentwith back pain. There are several infectious agentsimplicated, including—but not limited to—M. pneu-moniae, herpes viruses, rabies virus, hepatitis A virus,enteric fever and parasitic infections (eg,schistosoma).28 29

Spinal cord injurySpinal cord injury can usually be elicited from thehistory, and one should always ask about recent falls.Epidural abscess or haematoma may cause acute spinalcord compression and is usually associated with focalpain and can be shown radiologically. Anterior spinalartery occlusion may cause abrupt onset of acuteflaccid paraparesis and should always be consideredpostoperatively if there has been cardiothoracicsurgery requiring aortic clamping.

Box 2 Differential diagnoses for classic Guillain–Barré syndrome

Acute flaccid paralysisViruses targeting anterior horn cells or motor neurones▸ Poliomyelitis, non-polio enterovirus (enterovirus 71),

West Nile virus▸ Herpes simplex virus, cytomegalovirus, Epstein–Barr

virus, varicella zoster virus▸ Rabies virus, HIVTransverse myelitis▸ Mycoplasma pneumoniae▸ Herpes simplex virus, cytomegalovirus, Epstein–Barr

virus, varicella zoster virusSpinal cord injury▸ Acute spinal stenosis (eg, disc prolapse, epidural

abscess or haematoma)▸ Anterior spinal artery occlusionAcute peripheral neuropathies▸ Infections (eg, herpes simplex virus, HIV)▸ Consumption of toxins or poisons (eg, puffer fish poi-

soning (tetrodotoxin), lead, thallium, arsenic)▸ Tick paralysis, Lyme disease▸ PorphyriaNeuromuscular junction disorders▸ Myasthenia gravis▸ Lambert–Eaton myasthenic syndrome▸ BotulismNeuromuscular weakness related to critical illness▸ Critical illness neuropathy and myopathyMuscle disorders▸ Acute myositis▸ Periodic paralysis▸ Functional

REVIEW


Acute peripheral neuropathiesIn addition to GBS, clinicians should consider othercauses of acute peripheral neuropathy. Acute-onsetchronic inflammatory demyelinating polyradiculo-neuropathy is difficult to distinguish from GBS, butcan be diagnosed if there is deterioration after8 weeks from onset or more than three further dete-riorations during disease course.33 With the notableexception of diphtheritic neuropathy, which isdemyelinating-type and discussed later, most otheracute peripheral neuropathies are of axonal type.Numerous infectious agents can directly damage per-ipheral nerves (eg, HIV) and some have the additionalability to trigger GBS (eg, herpes simplex virus). Tickparalysis should be considered if endemic.34 A flu-likeprodrome lasting 5–10 days may be followed byrapidly progressive symmetric ascending flaccid par-alysis over 2–6 days. In Lyme disease,35 painful, oftenasymmetric polyradiculoneuropathy may occur severalmonths after initial tick bite or after a characteristicerythema migrans rash. Isolated or bilateral facialweakness has also been reported. CSF shows raisedlymphocytes and protein, and there is serological evi-dence of Lyme disease. Consumption of certain plants(eg, buckthorn)28 or intoxication with lead, arsenic36

or thallium have all caused a rapidly progressive poly-neuropathy mimicking GBS. Raw puffer fish (fugu) isa Japanese delicacy, but if prepared incorrectly mayresult in tetrodotoxin poisoning and rapidly progres-sive paralysis within hours of consumption.37

Currently, there is no antidote and treatment is sup-portive. Porphyric neuropathy38 is rare but sharesseveral clinical features with GBS, although usuallymore asymmetric. The onset can be acute and pro-gression to nadir occurs in 4 weeks. CSF also showsalbuminocytological dissociation, and nerve conduc-tion studies show an axonal-type neuropathy. In halfthe cases, the weakness starts in the upper limbs andmay therefore be confused with the pharyngeal-cervical-brachial variant. Invariably, patients reportsevere abdominal pain and show psychiatric symptomsor have seizures before developing porphyric neur-opathy. The diagnosis relies upon showing urinaryporphyrins under ultraviolet light or following expos-ure to oxygen.

Neuromuscular junction disordersAutoimmune diseases (eg, myasthenia gravis orLambert–Eaton myasthenic syndrome), exposure tocertain toxins (eg, botulinum toxin), consumption ofvarious plants (eg, hemlock) or indeed animal bites (eg,cobra or krait) result in neuromuscular dysfunctionand, in some cases, rapidly progressive paralysis in theabsence of sensory disturbance. In myasthenia gravis,there is usually also demonstrable muscle fatigability.

Neuromuscular weakness related to critical illnessNeurologists are frequently asked to assess patients onthe intensive care unit who develop generalised

weakness or are having difficulty weaning from mech-anical ventilation. Although GBS may develop in thissetting, neuromuscular weakness related to criticalillness should always be considered first.39 Clinicalassessment may be difficult as patients are often ence-phalopathic. Those receiving high-dose intravenousglucocorticoids (eg, for status asthmaticus) are at par-ticular risk of developing critical illness myopathy,which typically affects proximal more than distalmuscles and starts several days after treatment initi-ation. There is sometimes facial weakness althoughthe ocular muscles are usually spared. The serum cre-atine kinase is raised and nerve conduction studiesmay show slight motor nerve abnormalities. Patientswith severe sepsis may develop critical illness neur-opathy, which has a worse prognosis. Weakness isoften more distal and associated with sensory disturb-ance. Facial weakness is less common. The serum cre-atine kinase in these patients is usually normal andnerve conduction studies show a diffuse sensorymotor axonal polyneuropathy.39 Many patients haveboth critical illness myopathy and neuropathy andthese should be differentiated from cachectic myop-athy, which may develop in patients following pro-longed admission and is more slowly progressive.Prolonged use of neuromuscular blocking agents (eg,vecuronium bromide) also may lead to persistentweakness and failure to wean from the ventilator.

Muscle disordersAcute myositis may develop following certain viralinfections (eg, influenza A),40 and is associated withvariable degree of rhabdomyolysis. Typically, weaknessbegins within 2 weeks of the start of flu-like symp-toms. Patients often look unwell and report myalgiaand fever. On examination, the muscles are tender totouch, while sensation is normal. Serum creatinekinase is greatly elevated (often >10 000 U/L) andliver transaminases are also deranged. Urine dipstick ispositive for blood but there are no red blood cells onmicroscopy.Acute hypokalaemic periodic paralysis may mimic

GBS.41 Two-thirds of cases are due to the familialform, which is autosomal dominant, and typicallyaffects Caucasians. The paralysis often follows a highcarbohydrate meal or a prolonged period of exertion.Thyrotoxic periodic paralysis is more prevalentamong Asian, Hispanic and Native American males,and may be triggered by excess endogenous orexogenous thyroid hormones.

Functional illnessIt is not uncommon to see patients presenting to theemergency room with vague sensory symptoms orodd patterns of weakness, which can be difficult toexplain.42 In some patients, this may represent theearly stages of GBS, but instead are dismissed as func-tional, especially if the deep tendon reflexes are

REVIEW


present. By contrast, conversion disorder may be mis-taken for GBS, although patients rarely display thecore clinical features as described above.

Conditions mimicking MFS, Bickerstaff’s brainstemencephalitis and the pharyngeal-cervical-brachial variantof GBSAlthough MFS, Bickerstaff ’s brainstem encephalitisand the pharyngeal-cervical-brachial variant of GBSare rare, they should always be considered in patientspresenting to the emergency room with symptomsand signs suggesting progressive brainstem dysfunc-tion. Other neurological conditions, which commonlymimic these GBS variants include: brainstem stroke,myasthenia gravis, botulism, infective or inflammatoryrhombencephalitis and bacterial, carcinomatous orlymphomatous meningitis. Wernicke’s encephalopathyis the most important differential for patients withsuspected Bickerstaff ’s brainstem encephalitis (box 3).

Brainstem strokePosterior circulation or brainstem strokes produce avariety of well-described syndromes determined byspecific vascular territories. Some patients, forexample, those with vertebral artery dissection, maynot have risk factors for stroke, but instead mayreport recent neck injury (eg, whiplash) and presentwith neck pain. Typically, brainstem strokes are unilat-eral (eg, lateral medullary syndrome) unless the basilarartery is affected, in which case the ischaemic lesionoften localises to the mid-pons, where it extends fromthe paramedian pontine base to the tegmentum. Inmost patients, the symptoms are progressive and manyreport vertigo, nausea and headache, two or moreweeks beforehand.43 Limb weakness is usually asym-metric and often unilateral at onset. Facial and bulbarweakness and lower limb ataxia are also common.

Patients nearly always show eye signs: typically hori-zontal gaze paresis or internuclear ophthalmoplegia.Pontine lesions produce pinpoint pupils. Somepatients have pseudobulbar lability. ‘Top of basilar’strokes produce a different syndrome, with ischaemiclesions in the midbrain, thalami, temporal and occipi-tal lobes. The underlying cause is usually embolic.Sensation and weakness often remain intact, butpatients have problems with vertical gaze and conver-gence. The pupils are enlarged and react slowly orincompletely. Altered mentation, hallucinations andmemory problems may develop, depending on thearea of ischaemia.

Myasthenia gravisMyasthenia gravis is characterised by fluctuating weak-ness in voluntary muscles, which is made worse byexertion and often precipitated by certain drugs (eg,β-blockers) or systemic illness (eg, sepsis).44 Carefulhistory taking often shows that symptoms have beenpresent for some time. The presentation is highly vari-able, but there are four subtypes: generalised 50%,ocular 13%, ocular and bulbar 17%, and ocular andlimbs 20%. Commonly (85%), patients present withfluctuating ptosis or diplopia. Ptosis is often asymmet-ric and increases with prolonged upgaze and mayresolve with the ‘ice-pack’ test. The pupils are normal.Ophthalmoparesis often fluctuates from one examin-ation to the next, whereas in MFS or Bickerstaff ’sbrainstem encephalitis, ophthalmoparesis is progres-sive. Lateral rectus palsy is most frequent and thereforepatients often report horizontal diplopia. Facial weak-ness may also occur and weakness of eye closure (orbi-cularis oculi) may occur in isolation. Fifteen per cent ofpatients present with bulbar symptoms, which may beobvious or subtle; for example, with a history of fre-quent chest infections secondary to silent aspiration.Some patients present with head droop, which mayoccur in the pharyngeal-cervical-brachial variant ofGBS. Similarly, in myasthenia gravis, limb weakness isalso usually proximal and more obvious in the upperlimbs. The diagnosis of myasthenia gravis is usuallyclinical but often supported by the presence of serumanti-acetylcholine receptor antibodies (85% in generalmyasthenia gravis, <50% ocular myasthenia) andshowing decrement on low frequency (2–5 Hz) repeti-tive stimulation (75% generalised myasthenia gravis,<50% ocular myasthenia). Single-fibre electromyogra-phy is abnormal in >95% of patients but isnon-specific. Anti-MuSK (muscle-specific kinase) anti-bodies occur in 40% of anti-acetylcholine receptorantibody-negative patients with myasthenia gravis;these characteristically present with facial, bulbar,neck, and respiratory muscle weakness with relativesparing of ocular muscles.

Diphtheritic neuropathyApproximately 10% of patients with diphtheriadevelop neuropathy involving the cranial or

Box 3 Differential diagnoses for Miller Fisher syn-drome, Bickerstaff’s brainstem encephalitis andpharyngeal-cervical-brachial weakness

▸ Myasthenia gravis▸ Brainstem stroke (eg, basilar artery occlusion)▸ Diphtheritic neuropathy▸ Botulism▸ Rhombencephalitis

– Infective (eg, listeriosis, tuberculosis, brucellosis,Lyme disease, herpes simplex virus, Epstein–Barrvirus, JC virus, toxoplasmosis, cryptococcosis)

– Autoimmune (eg, multiple sclerosis, sarcoidosis,Behçet’s disease, systemic lupus erythematosus

– Malignancy (eg, lymphoma, paraneoplasticsyndrome)

▸ Basal meningitis (Inflammatory, infective, carcinomat-ous and lymphomatous)

REVIEW


peripheral nerves, which is demyelinating in natureand usually occurs within the first 2 months of infec-tion. Fever is usually present and in the vast majoritythere is bulbar dysfunction early in disease course.45

Wernicke’s encephalopathyWernicke’s encephalopathy results from thiamine defi-ciency and is often associated with chronic alcoholismin the setting of poor nutrition or increased metabolicrequirements (eg, systemic illness). Similar toBickerstaff ’s brainstem encephalitis, patients typicallypresent with differing degrees of encephalopathy,ocular dysfunction and ataxia.46 Rather than thehypersomnolence seen in Bickerstaff ’s brainstemencephalitis, patients are often profoundly disorien-tated and inattentive and appear indifferent to theirsurroundings. Gaze-evoked nystagmus is the most fre-quent ocular presentation. Although there may beophthalmoparesis, especially in the horizontal plane,this is usually incomplete unless Wernicke’s encephal-opathy is very severe. Ptosis is rare, and the pupils areoften sluggish or unreactive. Vestibular dysfunctionwithout hearing loss is also common. Gait ataxia maybe the first sign of Wernicke’s encephalopathy and isoften multifactorial in the alcoholic and, therefore,sometimes dismissed. Wernicke’s encephalopathy isprimarily a clinical diagnosis but supported by the pres-ence of characteristic changes on MR brain imaging.These include symmetric T2-signal change around thethird and fourth ventricles and the aqueduct and, inmost cases, also the mamillary bodies. Laboratory dem-onstration of thiamine deficiency is not always neededfor diagnosis, although thiamine status can be deter-mined by measuring whole blood levels, which is moresensitive than measurement of serum levels or theplasma transketolase method. Parenteral thiamine mustbe given early and should not be delayed in suspectedcases; it should be given before glucose to avoiddeterioration.

BotulismIntoxication with Clostridium botulinum toxin pro-duces a pattern of weakness similar to MFS and thepharyngeal-cervical-brachial variant of GBS, and isincreasingly seen in patients who inject black tarheroin. Interestingly, botulinum toxin type A, themost common cause of foodborne botulism, alsobinds to the gangliosides GQ1b and GT1a and maydisrupt the same population of neurons.47 48 In add-ition to ptosis, ophthalmoplegia and faciobulbarweakness, the pupils are characteristically dilated andpoorly reactive to light and accommodation.Descending paralysis in the absence of sensory dis-turbance may be complicated by respiratory failure, ifsevere. Some patients also develop autonomic symp-toms, including dry mouth, postural hypotension andconstipation. Foodborne botulism typically develops12–72 h after ingesting contaminated food (eg, home-canned vegetables) and weakness may be preceded by

nausea, vomiting and diarrhoea.49 Wound infectionswith C. botulinum spores, sometimes seen in drugusers from contaminated supplies, and colonisation ofthe small intestine in newborns can also rarely occur.The diagnosis is confirmed with mouse bioassay,which involves intraperitoneal injection of thepatient’s serum, gastric secretions or stool into amouse. The treatment is supportive and antitoxinshould be administered early in suspected cases.

RhombencephalitisBrainstem encephalitis (rhombencephalitis) should beamong the differential diagnosis in patients whodevelop rapidly progressive brainstem signs.50 Whenthere is underlying infection, patients characteristicallyreport headache, fever, nausea and vomiting, followedby brainstem, cerebellar and long tract signs.Respiratory depression and decreased consciousnessare common and seizures may also occur. In somepatients, meningeal symptoms are prominent and thisnarrows the differential further. Listeriosis is probablythe most common cause, especially in the immuno-compromised and among alcoholics or in healthy indi-viduals who have consumed heavily contaminatedfood. It may also complicate the third trimester ofpregnancy and lead to miscarriage. Its mortality is highand, therefore, ampicillin is often used empirically inpatients at risk. Other infective causes depending onpatients’ background should also be considered andinclude: tuberculosis, brucellosis, Lyme disease, herpessimplex virus, Epstein–Barr virus, JC virus, toxoplas-mosis and cryptococcosis. A wide range of non-infective conditions may produce similar symptoms,although systemic illness, especially fever, are often lessprominent.50 These include, but are not limited to:multiple sclerosis, sarcoidosis, Behçet’s disease, sys-temic lupus erythematosus, lymphoma and paraneo-plastic syndromes. Brainstem imaging is usuallyabnormal and there may be meningeal enhancement.CSF analysis, blood cultures and serological work-upare useful when abnormal or positive, but may be unre-vealing, which can delay the final diagnosis.

UNUSUAL PRESENTATIONS OF GBS, MFS ANDTHEIR SUBTYPES—CHAMELEONSAtypical forms of GBS and MFS can be difficult todiagnose, but should always be considered in thecontext of antecedent infection and monophasicdisease course. Most of these variants are exception-ally rare, except for hyper-reflexic GBS.

Hyper-reflexic GBSTo many neurologists, GBS is a disorder that affectsonly peripheral nerves and, therefore, is frequentlyoverlooked in the presence of normal or exaggerateddeep tendon reflexes. However, two large studies2 3

indicated that 10% of patients with GBS had normalor brisk reflexes throughout the course of illness.

REVIEW


Interestingly, these patients were more likely to presentwith pure motor weakness and, neurophysiologically,had features consistent with acute motor axonal neur-opathy rather than acute inflammatory demyelinatingpolyradiculoneuropathy. Patients with hyper-reflexicGBS also often have anti-GM1 or anti-GD1a anti-bodies.2 The term ‘hyper-reflexic variant’ of GBS hasbeen coined but we believe this is unnecessary. It isimportant to note that muscle tone is normal inpatients with hyper-reflexic GBS. The exact localisa-tion and mechanism which underpins hyper-reflexia inGBS remains unknown, but one theory is that antigan-glioside antibodies may cross the blood–brain–barrierand disrupt intramedullary interneurones.2

Paraparetic GBSThere is another unusual localised variant of GBS6–8

in patients who develop isolated flaccid lower limbweakness without neurological findings in the upperlimbs. In the cases described, bilateral ‘sciatic-like’ legpain was prominent and appeared early, undoubtedlycontributing to loss of leg function. Deep tendonreflexes were absent in the lower but not the upperlimbs and supported localisation to the lumbar nerveroots. Moreover, CSF albuminocytological dissoci-ation, normal routine laboratory findings and unre-markable MRI allowed differentiation from othercauses of lumbar polyradiculopathy, including diabetesmellitus, vasculitis, infiltrative or compressive lesionsand other infective agents. The diagnosis of so-calledparaparetic GBS is supported by showing axonal-typeneuropathy on nerve conduction studies, and the pres-ence of serum antiganglioside antibodies.7

Bifacial weakness with paraesthesiasThe bifacial weakness with paraesthesias variant ofGBS9 should always be considered in patients whodevelop bilateral facial weakness in the absence of oph-thalmoplegia or limb weakness. Most patients with thebifacial weakness with paraesthesias variant also reportdistal limb paraesthesias, elicited by careful sensoryexamination, allowing differentiation from other causesof bilateral facial weakness, including bilateral Bell’spalsy, Lyme disease and sarcoidosis. The diagnosis ofthe bifacial weakness with paraesthesias variant is alsosupported by the presence of antecedent infection, CSFalbuminocytological dissociation and evidence of per-ipheral nerve demyelination in the limbs.

Acute ataxic neuropathyTwo forms of incomplete MFS are characterised by pro-found ataxia in the absence of ophthalmoplegia.18 Inthe first, known as ataxic GBS, patients display ataxia inthe absence of both ophthalmoplegia and Rombergism.In the second, known as acute sensory ataxic neur-opathy, patients display ataxia in the absence of ophthal-moplegia but with Rombergism. To avoid nosologicalconfusion, ataxic GBS and acute sensory neuropathy are

grouped together and known collectively as acute ataxicneuropathy. Rather than being distinct entities, ataxicGBS and acute sensory ataxic GBS form a continuousspectrum, which is observed clinically and serologically.Patients with ataxic GBS are more likely to have anti-bodies against GQ1b, whereas monospecific IgGanti-GD1b antibodies without GQ1b reactivity aremore common in patients with acute sensory ataxicneuropathy.18 The mechanism for cerebellar-like ataxiain these patients is thought to be from selective involve-ment of muscle spindle afferents by anti-GQ1bantibodies.51

Acute ophthalmoparesis/acute ptosis/acute mydriasisThere are rare incomplete forms of MFS in patientswho develop isolated eye signs in association withanti-GQ1b antibodies, but without ataxia. In onestudy, 25% of 100 patients presenting with acuteabducens palsy had anti-GQ1b antibodies.52 Patientswho develop acute ophthalmoparesis19 may alsodevelop facial or rarely bulbar weakness, reinforcingthe concept that MFS is a spectrum of overlappingdisorders. Ptosis20 and mydriasis21 are not cardinalfeatures of MFS but may also appear in isolation andare associated with anti-GQ1b antibodies.

CONCLUSIONSGBS and its only variant, MFS, have several subtypes,which present in various ways and can be difficult todiagnose at first. The recognition of these subtypesbased on core clinical features (history of antecedentinfection, monophasic disease course, and symmetricalcranial or limb weakness) often allows differentiationfrom other causes of acute flaccid paraparesis orbrainstem syndromes. There are also more unusual

Key points

▸ GBS and MFS subtypes form a continuous spectrumof discrete and overlapping syndromes.

▸ GBS spectrum disorders should always be consideredif relatively symmetric limb or cranial nerve weaknessand ataxia, follow antecedent upper respiratory infec-tious symptoms or diarrhoea. This is supported bythe presence of distal paraethesias, CSF albuminocy-tological dissociation, abnormal nerve conductionstudies, or anti-ganglioside antibodies.

▸ GBS is very likely in patients who develop acuteflaccid paralysis with facial weakness.

▸ MFS and the pharyngeal-cervical-brachial variant ofGBS are frequently mistaken for myasthenia gravis,botulism or brainstem stroke.

▸ 10% of patients with GBS have normal or exagger-ated deep tendon reflexes.

REVIEW


localised forms of GBS and incomplete forms ofMFS, which should always be considered, as the prog-nosis is often favourable. Early correct diagnosis—especially in GBS, MFS, Bickerstaff ’s brainstemencephalitis and the pharyngeal-cervical-brachialvariant—is important and avoids unnecessary investi-gations and guides appropriate use of immunotherapy.

Contributors BRWresearched data for the article and draftedthe article. NY revised the article.

Funding Supported by Singapore National Medical ResearchCouncil (IRG 10nov086 and CSA/047/2012 to NY).

Competing interests None.

Provenance and peer review Commissioned; externally peerreviewed. This paper was reviewed by John Winer,Birmingham, UK.

REFERENCES1 Wakerley BR, Uncini A, Yuki N, and the GBS Classification

Group. Guillain-Barré and Miller Fisher syndromes – newdiagnostic classification. Nat Rev Neurol 2014;10:537–44.

2 Yuki N, Kokubun N, Kuwabara S, et al. Guillain-Barrésyndrome associated with normal or exaggerated tendonreflexes. J Neurol 2012;259:1181–90.

3 Fokke C, van den Berg B, Drenthen J, et al. Diagnosis ofGuillain-Barré syndrome and validation of Brighton criteria.Brain 2014;137:33–43.

4 Mori M, Kuwabara S, Fukutake T, et al. Clinical features andprognosis of Miller Fisher syndrome. Neurology2001;56:1104–6.

5 Wakerley BR, Yuki N. Pharyngeal-cervical-brachial variant ofGuillain-Barré syndrome. J Neurol Neurosurg Psychiatry2014;85:339–44.

6 Ropper AH. Further regional variants of acute immunepolyneuropathy: bifacial weakness or sixth nerve paresis withparesthesias, lumbar polyradiculopathy, and ataxia withpharyngeal-cervical-brachial weakness. Arch Neurol1994;51:671–5.

7 Nagashima T, Kokubun N, Shahrizaila N, et al. ParapareticGuillain-Barré syndrome: extending the axonal spectrum.Neurol Clin Neurosci 2013;1:224–6.

8 van den Berg B, Fokke C, Drenthen J, et al. ParapareticGuillain-Barré syndrome. Neurology 2014;82:1984–9.

9 Susuki K, Koga M, Hirata K, et al. A. Guillain-Barré syndromevariant with prominent facial diplegia. J Neurol2009;256:1899–905.

10 Fisher M. An unusual variant of acute idiopathic polyneuritis(syndrome of ophthalmoplegia, ataxia and areflexia). N Engl JMed 1956;255:57–65.

11 Bickerstaff ER. Brain-stem encephalitis; further observations on agrave syndrome with benign prognosis. Br Med J 1957;1:1384–7.

12 Koga M, Yuki N, Hirata K. Antecedent symptoms in Guillain-Barré syndrome: an important indicator for clinical andserological subgroups. Acta Neurol Scand 2001;103:278–87.

13 Poropatich KO, Walker CL, Black RE. Quantifying theassociation between Campylobacter infection andGuillain-Barré syndrome: a systematic review. J Health PopulNutr 2010;28:545–52.

14 Allos BM. Association between Campylobacter infection andGuillain-Barré syndrome. J Infect Dis 1997;176:S125–8.

15 Takahashi M, Koga M, Yokoyama K, et al. Epidemiology ofCampylobacter jejuni isolated from patients with

Guillain-Barré and Fisher syndromes in Japan. J Clin Microbiol2005;43:335–9.

16 Wakerley BR, Yuki N. Infectious and noninfectious triggers inGuillain-Barré syndrome. Expert Rev Clin Immunol2013;9:627–39.

17 Ropper AH. The Guillain-Barré syndrome. N Engl J Med1992;326:1130–6.

18 Ito M, Matsuno K, Sakumoto Y, et al. Ataxic Guillain-Barrésyndrome and acute sensory ataxic neuropathy form acontinuous spectrum. J Neurol Neurosurg Psychiatry2011;82:294–9.

19 Yuki N, Odaka M, Hirata K. Acute ophthalmoparesis (withoutataxia) associated with anti-GQ1b IgG antibody: clinicalfeatures. Ophthalmology 2001;108:196–200.

20 Yuki N, Koga M, Hirata K. Isolated internal ophthalmoplegiaassociated with immunoglobulin G anti-GQ1b antibody.Neurology 1998;51:1515–16.

21 Jindal G, Parmar VR, Gupta VK. Isolated ptosis as acuteophthalmoplegia without ataxia, positive for anti-GQ1bimmunoglobulin G. Pediatr Neurol 2009;41:451–2.

22 Kuitwaard K, van Koningsveld R, Ruts L, et al. RecurrentGuillain-Barré syndrome. J Neurol Neurosurg Psychiatry2009;80:56–9.

23 Sejvar JJ, Kohl KS, Gidudu J, et al. Guillain-Barré syndromeand Fisher syndrome: case definitions and guidelines forcollection, analysis, and presentation of immunization safetydata. Vaccine 2011;29:599–612.

24 Ruts L, van Koningsveld R, van Doorn PA. Distinguishingacute-onset CIDP from Guillain-Barré syndrome withtreatment related fluctuations. Neurology 2005;65:138–40.

25 Hughes RA, Swan AV, van Doorn PA. Intravenousimmunoglobulin for Guillain-Barré syndrome. CochraneDatabase Syst Rev 2010:CD002063.

26 Ito M, Kuwabara S, Odaka M, et al. Bickerstaff ’s brainstemencephalitis and Fisher syndrome form a continuous spectrum:clinical analysis of 581 cases. J Neurol 2008;255:674–82.

27 Nishimoto Y, Odaka M, Hirata K, et al. Usefulness ofanti-GQ1b IgG antibody testing in Fisher syndrome comparedwith cerebrospinal fluid examination. J Neuroimmunol2004;148:200–5.

28 Marx A, Glass JD, Sutter RW. Differential diagnosis of acuteflaccid paralysis and its role in poliomyelitis surveillance.Epidemiol Rev 2000;22:298–316.

29 Cho TA, Vaitkevicius H. Infectious myelopathies. Continuum(Minneap Minn) 2012;18:1351–73.

30 Howard RS. Poliomyelitis and the postpolio syndrome. BMJ2005;330:1314–18.

31 Solomon T, Lewthwaite P, Perera D, et al. Virology,epidemiology, pathogenesis, and control of enterovirus 71.Lancet Infect Dis 2010;10:778–90.

32 Gadre G, Satishchandra P, Mahadevan A, et al. Rabies viralencephalitis: clinical determinants in diagnosis with specialreference to paralytic form. J Neurol Neurosurg Psychiatry2010;81:812–20.

33 Ruts L, Drenthen J, Jacobs BC, et al. Dutch GBS Study Group.Distinguishing acute-onset CIDP from fluctuating Guillain-Barrésyndrome: a prospective study.Neurology 2010;74:1680–6.

34 Pecina CA. Tick paralysis. Semin Neurol 2012;32:531–2.35 Shapiro ED. Clinical practice. Lyme disease. N Engl J Med

2014;370:1724–31.36 Donofrio PD, Wilbourn AJ, Albers JW, et al. Acute arsenic

intoxication presenting as Guillain-Barré-like syndrome. MuscleNerve 1987;10:114–20.

REVIEW


37 Kaji R, Nodera H. Puffer fish poisoning, Guillain-Barrésyndrome and persistent sodium channels. Ann Neurol2005;57:309.

38 Albers JW, Fink JK. Porphyric neuropathy. Muscle Nerve2004;30:410–22.

39 Latronico N, Rasulo FA. Presentation and management of ICUmyopathy and neuropathy. Curr Opin Crit Care2010;16:123–7.

40 Oba K, Nishihara A, Okamura K, et al. Two cases of acutemyositis associated with influenza A virus infection in theelderly. J Nippon Med Sch 2000;67:126–9.

41 Maurya PK, Kalita J, Misra UK. Spectrum of hypokalaemicperiodic paralysis in a tertiary care centre in India. PostgradMed J 2010;86:692–5.

42 Stone J, Carson A, Sharpe M. Functional symptoms and signsin neurology: assessment and diagnosis. J Neurol NeurosurgPsychiatry 2005;76:i2–12.

43 Ferbert A, Brückmann H, Drummen R. Clinical featuresof proven basilar artery occlusion. Stroke1990;21:1135–42.

44 Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis:emerging clinical and biological heterogeneity. Lancet Neurol2009;8:475–90.

45 Sechi G, Serra A. Wernicke’s encephalopathy: new clinicalsettings and recent advances in diagnosis and management.Lancet Neurol 2007;6:442–55.

46 Logina I, Donaghy M. Diphtheritic polyneuropathy: a clinicalstudy and comparison with Guillain-Barré syndrome. J NeurolNeurosurg Psychiatry 1999;67:433–8.

47 Kitamura M, Iwamori M, Nagai Y. Interaction betweenClostridium botulinum neurotoxin and gangliosides. BiochimBiophys Acta 1980;628:328–35.

48 Kamata Y, Kozaki S, Sakaguchi G, et al. Evidence for directbinding of Clostridium botulinum type E derivative toxin andits fragments to gangliosides and free fatty acids. BiochemBiophys Res Commun 1986;140:1015–19.

49 Sobel J. Botulism. Clin Infect Dis 2005;41:1167–73.50 Moragas M,Martínez-Yélamos S, Majós C, et al. Rhombencephalitis:

a series of 97 patients.Medicine (Baltimore) 2011;90:256–61.51 Liu JX, Willison HJ, Pedrosa-Domellof F. Immunolocalization

of GQ1b and related gangliosides in human extraocularneuromuscular junctions and muscle spindles. InvestOphthalmol Vis Sci 2009;50:3226–32.

52 Tatsumoto M, Odaka M, Hirata K, et al. Isolated abducensnerve palsy as a regional variant of Guillain-Barré syndrome.J Neurol Sci 2006;243:35–8.

REVIEW


mimics and chameleons in guillain-barre and miller fisher syndromes

Documents