Anti-GQ1b IgG antibody syndrome: clinical andimmunological range

M Odaka, N Yuki, K Hirata

AbstractObjectives—To clarify the nosological re-lation among Miller Fisher syndrome(MFS), Guillain-Barré syndrome (GBS)with ophthalmoplegia, BickerstaV’s brainstem encephalitis (BBE), and acute oph-thalmoparesis without ataxia. Serumsamples from patients with each conditionoften have anti-GQ1b IgG antibody.Methods—Information on antecedent ill-ness, initial symptoms, neurological signsduring the illness, and CSF findings werereviewed in 194 patients with anti-GQ1bIgG. It was determined whether overlap-ping MFS and GBS (MFS/GBS), as well asoverlapping BBE and GBS (BBE/GBS), isexplained by the combined action of anti-GQ1b IgG and anti-GM1 or anti-GD1aIgG, serological markers of GBS.Results—Based on the diagnostic criteria,all the patients with acute ophthal-moparesis, MFS, MFS/GBS, BBE/GBS,and BBE had external ophthalmoplegia;all the patients with MFS, MFS/GBS, orGBS had hyporeflexia or areflexia; and allthose with MFS and BBE showed ataxia.Tendon reflexes were decreased or absentin 91% of those with BBE/GBS, 67% ofthose with BBE, and 53% of those withacute ophthalmoparesis. Ataxia waspresent in 68% of the patients withMFS/GBS and 45% of those with BBE/GBS. Antecedent illness caused by upperrespiratory tract infection had occurredin 60% to 80% of these patients, and CSFalbuminocytological dissociation in 25%to 75%. Anti-GM1 or anti-GD1a IgG waspresent in 50% of those with GBS, 35% ofthose with MFS/GBS, 27% of those withBBE/GBS, 16% of those with MFS, and 8%of those with BBE.Conclusions—These findings togetherwith the common autoantibody (anti-GQ1b IgG) suggest that a common au-toimmune mechanism functions in thepathogenesis of these illnesses. In a largerstudy, it was confirmed clinically thatMFS, GBS, BBE, and acute ophthal-moparesis are closely related, forming acontinuous range. This is supported bythe immunological findings. The term“anti-GQ1b IgG antibody syndrome” isnot intended to be used as a clinical diag-nosis, but recognition of this syndrome isuseful for understanding the aetiologicalrelation among the various illnesses andfor introducing the established treatmentsof GBS for use with other conditions.(J Neurol Neurosurg Psychiatry 2001;70:50–55)

Keywords: anti-GQ1b IgG antibody; Miller Fisher syn-drome; Guillain-Barré syndrome; BickerstaV’s brainstem encephalitis; ophthalmoplegia

Miller Fisher syndrome (MFS) is characterisedby the acute onset of external ophthalmople-gia, ataxia of a cerebellar type, and the loss oftendon reflexes.1 It is considered a variant ofGuillain-Barré syndrome (GBS), becausesome patients who present with MFS progressto GBS.2 Chiba et al3 found that all of sixpatients with MFS had serum IgG antibody toGQ1b ganglioside during the acute phase ofthe illness, whereas none of 16 patients withGBS had it. We found anti-GQ1b IgGantibody in one of 15 patients with GBS whohad impaired abduction in the right eye.4 Chibaet al5 subsequently detected anti-GQ1b IgG infive of six patients with GBS who showedexternal ophthalmoplegia, whereas none of 23patients with GBS without ophthalmoplegiahad the autoantibody. Furthermore, anti-GQ1b IgG was present in all of five patientswith acute postinfectious ophthalmoplegiawithout ataxia, “atypical MFS” in their desig-nation. Case reports of paresis of the extraocu-lar muscles without ataxia, which is of acuteonset and self limited have been published.6 7

Such patients usually have had antecedentinfections or immunisations. We designatedthis condition “acute ophthalmoparesis” andreported that all of eight patients with acuteophthalmoparesis had anti-GQ1b IgG.8 Theautoantibody titres in acute ophthalmoparesisdid not diVer significantly from those in MFS.The existence of acute ophthalmoparesis casessupports the conclusion of Chiba et al5 thatanti-GQ1b IgG is associated closely withexternal ophthalmoplegia. Kusunoki et al9

reported that five of 149 patients with anti-GQ1b IgG had ataxia without ophthalmople-gia and stated that anti-GQ1b IgG is associatedwith ataxia as well as ophthalmoplegia.

Murine monoclonal anti-GQ1b antibodystrongly stains the paranodal regions of theextramedullary portion of human oculomotor,trochlear, and abducens nerves, and weaklystains the deep cerebellar nuclei.5 In patientswith MFS those nerves were enhanced bygadolinium on MRI.10 11 Campylobacter jejuni,cytomegalovirus, Epstein-Barr virus, and Strep-tococcus pyogenes have been reported as ante-cedent infectious agents in MFS.12 Koga et al13

showed serological evidence of C jejuni infec-tion in 12 (18%) of 65 patients with MFS, andthe GQ1b epitope is present in the lipopolysac-charide of C jejuni isolated from patients withMFS.14 Infection by C jejuni that bears GQ1b-like lipopolysaccharide may trigger production

J Neurol Neurosurg Psychiatry 2001;70:50–5550

Department ofNeurology, DokkyoUniversity School ofMedicine,Kitakobayashi 880,Mibu, Shimotsuga,Tochigi 321–0293,JapanM OdakaN YukiK Hirata

Correspondence to:Dr Yukiyuki@dokkyomed.ac.jp

Received 10 May 2000 andin revised form21 July 2000Accepted 15 August 2000

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of anti-GQ1b IgG antibody in some patientswith MFS, whose autoantibody may then bindto the ocular motor nerves and to the deep cer-ebellar nuclei causing ophthalmoplegia andcerebellar ataxia.

BickerstaV et al15 16 described patients whoexperienced acute onset of external ophthal-moplegia and cerebellar ataxia, a syndrome,although severe, which had a benign prognosis.Patients showing drowsiness, brisk reflexes,extensor plantar responses, and hemisensorydisturbance or CSF pleocytosis usually areconsidered to have BickerstaV’s brain stemencephalitis (BBE) rather than MFS. OpinionsdiVer, however, as to whether these are distinctor related conditions. We found that all of threepatients with BBE had high anti-GQ1b IgGantibody titres which decreased with clinicalimprovement.17 The fact that BBE and MFSshare common autoantibodies suggests thatthey are closely related, not distinct, condi-tions. The anti-GQ1b IgG antibody titres inBBE did not diVer significantly from those inMFS. By contrast, BickerstaV and Cloake15

speculated that the aetiology of BBE is similarto that of GBS because they detected areflexiaand CSF albuminocytological dissociation. Wereported necropsy findings for a patient inwhom limb weakness associated with BBE hadbeen diagnosed clinically.18 The peripheralnerves showed moderate to severe loss of largemyelinated fibres. The pathological findingssupported the original hypothesis by Bicker-staV and Cloake15 that BBE is closely related toGBS. That patient had anti-GQ1b IgG. Somepatients with GBS have coma associated withthe absence of oculocephalic reflex.18 Theexistence of such cases supports the hypothesisof BickerstaV and Cloake15 that BBE is closelyrelated to GBS.

We earlier proposed that MFS, GBS withophthalmoplegia, acute ophthalmoparesis, andBBE should all be designated “anti-GQ1b IgGantibody syndrome” to clarify their nosologicalrelations. The first aim of this larger study wasto test our hypothesis that these are relatedconditions that form a continuous range. Thesecond was to determine whether overlapping

MFS and GBS, as well as overlapping BBE andGBS, can be explained by the combined actionof anti-GQ1b IgG with anti-GM1 or anti-GD1a IgG, serological markers of GBS.19 20

Materials and methodsPATIENTS

Serum samples obtained from patients withvarious neurological disorders including motorneuron disease, multifocal motor neuropathy,and chronic inflammatory demyelinatingpolyneuropathy were referred to us fromuniversity and district general hospitals forantiganglioside antibody assays. Serum anti-bodies to GM1, GM2, GD1a, GD1b, GT1b,and GQ1b were measured using the enzymelinked immunosorbent assay (ELISA) de-scribed elsewhere.21 Serum was consideredpositive when the antibody titre was 500 ormore. Anti-GQ1b IgG antibody was positive inthe samples from 245 patients tested betweenDecember 1994 and September 1998. Medicalrecords of the patients were reviewed by one ofus (MO). Information on antecedent illness,initial symptoms, neurological signs during theillness, and CSF findings were obtained from194 patients. The following signs were as-sessed: consciousness disturbance; blepharop-tosis, internal or external ophthalmoplegia,nystagmus, facial weakness, and bulbar palsy;limb weakness (<3 on the Medical ResearchCouncil scale); Babinski’s sign; deep tendonreflexes (brisk, normal, decreased, or absent);truncal or limb ataxia; and deep or superficialsense impairment. In the present study, thealbuminocytological dissociation was definedas high CSF protein (>45 mg/dl) with normalcellularity (<5/µl ).

DIAGNOSTIC CRITERIA

The diagnosis of GBS was based on the estab-lished clinical criteria, and extensor plantarresponses do not exclude the diagnosis if otherfeatures are typical.22 The diagnostic criteriaused for MFS, BBE, and acute ophthal-moparesis are given in table 1. Patients whoshowed limb weakness, in addition to ophthal-moparesis and ataxia, were considered to have

Table 1 Diagnostic criteria for Miller Fisher syndrome, BickerstaV’s brain stem encephalitis, and acute ophthalmoparesis

Features required for diagnosisMiller Fisher syndrome:

Progressive, relatively symmetric ophthalmoplegia and ataxia by 4 weeksHyporeflexia or areflexiaLimb strength with 5 or 4 on the Medical Research Council scale

BickerstaV’s brain stem encephalitis:Progressive, relatively symmetric ophthalmoplegia and ataxia by 4 weeksEither consciousness disturbance (coma, semicoma, or stupor) or pyramidal signs (hyperreflexia or pathological reflexes)Limb strength with 5 or 4 on the Medical Research Council scale

Acute ophthalmoparesis:Progressive, relatively symmetric ophthalmoplegia by 4 weeksNeither ataxia nor limb weakness

Features strongly supportive of the diagnosis for each conditionA history of infectious symptoms within 4 weeks before the onset of neurological symptomsCSF albuminocytological dissociationPresence of anti-GQ1b IgG antibody

Features that rule out the diagnosisWernicke’s encephalopathy, vascular disease involving the brain stem, multiple sclerosis, neuro-Behçet’s disease, botulism,

myasthenia gravis, brain stem tumour, pituitary apoplexy, vasculitis, and lymphomaAppendix

Patients showing limb weakness (3 or less on the Medical Research Council scale), in addition to ophthalmoplegia and ataxia,were diagnosed as having overlapping Miller Fisher syndrome and Guillain-Barré syndrome.

Patients showing limb weakness (<3 on the Medical Research Council scale), in addition to consciousness disturbance (coma,semicoma, or stupor) or pyramidal signs as well as ophthalmoplegia, were diagnosed as having overlapping BickerstaV’s brainstem encephalitis and Guillain-Barré syndrome.

Anti-GQ1b IgG antibody syndrome 51

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overlapping MFS and GBS (MFS/GBS).Patients who showed limb weakness, in addi-tion to consciousness disturbance (coma,semicoma, or stupor) or pyramidal sign as wellas ophthalmoparesis and ataxia, were consid-ered to have overlapping BBE and GBS (BBE/GBS).

STATISTICAL ANALYSIS

Analyses were performed with Stat ViewVersion 4.5-J software (Abacus Concepts, Ber-keley, CA, USA). DiVerences in proportionswere tested by the ÷2 test or Fisher’s exact test(two tailed). A p value<0.05 was used forsignificance in all the comparisons.

ResultsCLINICAL FEATURES OF ANTI-GQ1B IGG ANTIBODY

SYNDROME

Clinical profiles of the 194 patients (medianage 37; 106 men; 88 women) are shown in table2. Ninety four per cent had antecedent illnesses(upper respiratory tract infection alone 75%;diarrhoea alone 9%; both upper respiratorytract infection and diarrhoea 5%). As initialsymptoms respectively, 130 patients (67%) and56 patients (29%) complained of diplopia andgait disturbance, and 25 patients (13%) hadboth. Consciousness was disturbed in 11%(drowsiness 7%; stuporous or comatose 4%).External ophthalmoplegia was present in 91%and ataxia in 80% (both truncal and limb 50%;truncal alone 20%; limb alone 10%). Of 155patients who had ataxia, 41 (26%) had deep

sense impairment. Limb weakness was appreci-able in 26% of the 194 patients. Deep tendonreflexes were absent in 60% of them, decreasedin 30%, normal in 6%, and brisk in 4%. Exten-sor plantar response was present in 8%, andhyperreflexia or the Babinski’s sign in 9%.Patients with external ophthalmoplegia hadassociated ataxia (p<0.0001; odds ratio 33.7;95% confidence interval 8.1–139.6), whereasneither ophthalmoplegia nor ataxia were asso-ciated with hyporeflexia or areflexia (p=0.8 andp=0.5 respectively). Fifty eight per cent hadCSF albuminocytological dissociation.

CLINICAL FEATURES OF EACH DIAGNOSTIC

CONDITION

The diagnosis of MFS was made for 110(57%), MFS/GBS for 31 (16%), acute oph-thalmoparesis for 15 (8%), BBE for 12 (6%),BBE/GBS for 11 (6%), and GBS for eight(4%). The illnesses of the other seven (4%)were unclassified. Among the patients includedin this study, illustrative cases of acute ophthal-moparesis,23 MFS,10 BBE,24 and MFS/GBS25

have been reported previously. An illustrativecase of BBE/GBS is described below.

Case report of BBE/GBSA 24 year old man had a cough and nasalobstruction which abated over a few days. Oneweek after resolution of this illness, heexperienced diplopia and numbness of thearms (day 1). On day 2, he was unable to stand.He became drowsy with dysarthria, and was

Table 2 Clinical profiles of patients with anti-GQ1b IgG antibody

TotalAcuteophthalmoparesis MFS MFS/GBS GBS BBE/GBS BBE Unclassified

Patients (n) 194 15 110 31 8 11 12 7Sex (men/women) 106/88 6/9 66/44 16/15 4/4 5/6 5/7 4/3Median age (range) 37 (2–78) 30 (9–69) 41 (2–78) 33 (6–76) 36 (17–50) 42 (24–76) 37 (27–69) 31 (18–66)Antecedent illness: (%) (%) (%) (%) (%) (%) (%) (%)

Upper respiratory infection 80 60 86 74 63 82 75 71Diarrhoea 14 27 10 19 63 0 0 14

Initial symptoms:Diplopia 67 100 75 39 0 55 75 71Gait disturbance 29 0 32 42 75 18 33 43Limb weakness 12 0 3 35 100 9 0 14Photophobia 8 0 10 10 0 0 0 14Dysarthria 7 7 4 16 0 18 8 14Dysphagia 2 0 2 3 0 0 0 0Dysaesthesia 4 0 3 10 13 9 0 0Blepharoptosis 2 0 3 0 0 0 8 0Consciousness disturbance 1 0 0 0 0 9 8 0

Neurological signs during the course of the illness:Consciousness disturbance

Drowsiness 7 0 3 13 0 36 17 0Stupor, semicoma, coma 4 0 0 0 0 27 33 0

Blepharoptosis 45 40 51 42 0 36 17 29External ophthalmoplegia 91 100 100 100 0 100 100 100Internal ophthalmoplegia 36 7 37 52 0 27 42 29Nystagmus 22 27 16 29 25 18 33 57Facial weakness 34 13 23 71 13 82 33 14Bulbar palsy 29 13 20 61 13 82 25 14Limb weakness* 26 0 0 100 100 100 0 14Tendon reflex

Brisk 4 0 0 0 0 9 33 0Normal 6 47 0 0 0 0 0 100Decreased 30 33 29 32 62 35 25 0Absent 60 20 71 68 38 56 42 0

Babinski’s sign 8 0 0 0 0 64 67 0Ataxia 80 0 100 68 0 45 100 100Deep sense impairment 26 0 27 39 13 55 8 29Superficial sense impairment 35 20 36 42 38 36 8 29CSF albuminocytological dissociation 58 25 66 43 25 75 42 80

MFS= Miller Fisher syndrome; GBS=Guillain-Barré syndrome; BBE=BickerstaV’s brain stem encephalitis; MFS/GBS=overlapping Miller Fisher syndrome andGuillain-Barré syndrome; BBE/GBS=overlapping BickerstaV’s brain stem encephalitis and Guillain-Barré syndrome.* 3 or less on the Medical Research Council scale

52 Odaka, Yuki, Hirata

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admitted to a hospital on day 3. On admission,he was stuporous. Bilateral blepharoptosis,limitation of ocular movement in all directions,bilateral facial palsy, and slurred speech werenoted. Light reflexes were prompt. Distaldominant weakness in the four limbs wasscored 3 on the Medical Research Councilscale. Deep tendon reflexes were absent, butextensor plantar responses remained. Finger tonose and heel to knee tests showed dysmetriaand decomposition. Hypaesthesia of the gloveand stocking type was present. Protein in CSFwas 27 mg/dl with 1 cell/µl on day 7, and 295mg/dl with 6 cells/µl on day 14. Seven sessionsof immunoadsorption therapy were given ondays 3, 4, 5, 7, 9, 11, and 13. In Japan, thepatients with GBS and related disorders oftenreceive immunoadsorption using a tryptophanconjugated column (TR-350, Asahi Medical,Japan) which highly absorbs anti-GQ1b IgG.26

On day 6, he began to recover consciousness,and limb weakness diminished. He could walkwithout support on day 19, and diplopia disap-peared on day 39.

Table 2 shows the antecedent illness, initialsymptoms, and neurological signs for eachcondition. For antecedent illness, the fre-quency of upper respiratory tract infection wasmuch higher than that of diarrhoea for all theconditions except GBS. As the initial symp-tom, diplopia was experienced in 100% of thepatients with acute ophthalmoparesis, 75% ofthose with both MFS and BBE, 55% of thosewith BBE/GBS, and 39% of those withMFS/GBS. Gait disturbance was experiencedby 75% of the patients with GBS, 42% of thosewith MFS/GBS, 33% of those with BBE, 32%of those with MFS, and 18% of those withBBE/GBS. On the basis of the diagnostic crite-ria, all the patients with acute ophthalmopare-sis, MFS, MFS/GBS, BBE/GBS, and BBE hadexternal ophthalmoplegia; all the patients withMFS, MFS/GBS, and GBS had hyporeflexia orareflexia; and all the patients with MFS andBBE had ataxia. Tendon reflexes were de-creased or absent in 91% of those withBBE/GBS, 67% of those with BBE, and 53% ofthose with acute ophthalmoparesis. Ataxia waspresent in 68% of the patients with MFS/GBSand 45% of those with BBE/GBS. Conscious-ness was altered in 63% of the patients withBBE/GBS, 50% of those with BBE, 13% ofthose with MFS/GBS, and 3% of those withMFS. Albuminocytological dissociation inCSF was present in 75% of the patients withBBE/GBS, 66% of those with MFS, 43% ofthose with MFS/GBS, 42% of those with BBE,

and 25% of those with acute ophthalmoparesisand GBS.

ANTI-GM1 OR ANTI-GD1a IgG IN EACH DIAGNOSTIC

CONDITION

Table 3 shows the immunological range for allthe conditions. Anti-GM1 IgG antibody waspresent in 38% of the patients with GBS, 16%of those with MFS/GBS, 8% of those withBBE, and 5% of those with MFS. Anti-GD1aIgG antibody was present in 50% of thepatients with GBS, 29% of those with MFS/GBS, 27% of those with BBE/GBS, 13% ofthose with MFS, and 8% of those with BBE.Anti-GM1 or anti-GD1a IgG antibody waspresent in 50% of the patients with GBS, 35%of those with MFS/GBS, 27% of those withBBE/GBS, 16% of those with MFS, and 8% ofthose with BBE. Neither anti-GM1 noranti-GD1a IgG was present in acute ophthal-moparesis.

DiscussionOUR DIAGNOSTIC CRITERIA FOR MFS AND BBE

One of the three patients originally describedby Fisher1 showed mild drowsiness. Drowsi-ness therefore may accompany both MFS andBBE according to the criteria used in thisstudy. All of the three cases reported by Fisherfulfilled our criteria for MFS, but not for BBE,whereas six of eight cases described by Bicker-staV16 fulfilled our criteria for BBE, but not forMFS. In case 4 reported by BickerstaV16 thepatient showed gross flaccid weakness. Thatcondition was diagnosed as BBE/GBS basedon our criteria. Because another patient (case6) did not show ophthalmoplegia, neither thecriteria for MFS nor BBE were fulfilled.

Al-Din et al27 (with BickerstaV) reported 18patients with BBE (11 with drowsiness, onewith coma). Tendon reflexes were absent in 11of them, normal in three, and brisk in four.Babinski’s sign was positive in five patients, anddeep tendon reflexes were normal in one andabsent in one. Ropper28 criticised this reportand considered that six of the cases were typi-cal MFS and the other 12 obscure brain stemlesions without peripheral neuropathy. Basedon our criteria, MFS would have beendiagnosed in six cases (cases 3, 5, 11, 13, 15,and 16) and BBE in 12. Our criteria thereforeshould prove useful for making clinical diag-noses of MFS and BBE. Later, Al-Din et al29

(without BickerstaV) diagnosed MFS in threecomatose patients who showed ophthalmople-gia, ataxia, and areflexia. Patients 2 and 3showed tetraplegia. Based on our criteria, case1 in their report would be BBE and cases 2 and3 BBE/GBS. Among our patients primary phy-sicians had diagnosed four cases of “MFSassociated with hyperreflexia” which, in thisstudy, were diagnosed as BBE.

CLINICALLY CONTINUOUS RANGE OF MFS, GBS,BBE, AND ACUTE OPHTHALMOPARESIS

One hundred and forty two (73%) of the 194patients with anti-GQ1b IgG fulfilled the crite-ria for the syndrome of ophthalmoplegia,ataxia, and areflexia according to Al-Din et al30;whereas 110 had MFS, 21 MFS/GBS, six

Table 3 Antiganglioside IgG antibodies in each condition

Diagnosis No

IgG antibodies to:

GM2(%)

GM1(%)

GD1a(%)

GD1b(%)

GT1b(%)

GM1 or GD1a(%)

Acute ophthalmoparesis 15 0 0 0 7 0 0MFS 110 1 5 13 15 2 16MFS/GBS 31 10 16 29 35 13 35GBS 8 25 38 50 50 50 50BBE/GBS 11 9 0 27 36 27 27BBE 12 0 8 8 17 0 8Unclassified 7 0 0 14 14 14 0

Abbreviations as for table 2.

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BBE, and five BBE/GBS according to our cri-teria. All the patients with MFS fulfilled thecriteria for the syndrome of ophthalmoplegia,ataxia, and areflexia, whereas only 68% ofthose with MFS/GBS, 50% of those with BBE,and 45% of those with BBE/GBS did. Thesefindings indicate considerable overlapping ofthe syndrome of ophthalmoplegia, ataxia, andareflexia and anti-GQ1b IgG syndrome. Thepatients with anti-GQ1b IgG, however, had astatistically significant correlation only betweenophthalmoplegia and ataxia. Neither ophthal-moplegia nor ataxia was correlated withareflexia. This is further support for the earlierreport that ophthalmoplegia and ataxia areassociated closely with anti-GQ1b IgG.5 9

Anti-GQ1b IgG antibody syndrome comprisesa wide range presenting with ophthalmoplegiaand ataxia. Chemical analysis showed that theoptic nerves and the oculomotor, trochlear,and abducens nerves had similar concentrationof GQ1b.31 The GQ1b epitope localisationsuggested immunohistochemically, however,was diVerent: no accumulation of staining inthe specific region of the optic nerve. Theirfindings could explain why none of our patientswho had anti-GQ1b IgG antibody showedoptic neuropathy.

Seven patients were unclassified by the crite-ria we used. They had ophthalmoplegia andataxia, but their tendon reflexes were normalduring the illness. We elsewhere reported onfour patients with Campylobacter neuropathyassociated with anti-GM1 IgG, in whom mus-cle stretch reflexes were preserved or hyperac-tive throughout the illness.32 Although loss oftendon jerks is a valuable diagnostic feature ofGBS, the presence of such unclassified casessuggests that the diagnostic criteria should beextended because this loss also could apply toMFS; therefore, those cases could be diag-nosed as MFS. The other cases could be diag-nosed as BBE because three of the 18 patientsreported by Al-Din et al27 showed normal mus-cle stretch reflexes. Furthermore, the sevenunclassified cases could be considered as over-lapping MFS and BBE. The existence of suchcases also supports the hypothesis that theseconditions form a continuous range and thatophthalmoplegia and ataxia are more impor-tant than areflexia in that range. Thirty onecases of MFS/GBS and 11 cases of BBE/GBSwere reported in this study. The existence of

these overlapping cases strongly supports theidea of continuity between MFS and GBS, aswell as between BBE and GBS.2 18

Double vision was an initial symptom inthree of four of the patients with both MFS andBBE, and gait disturbance in one of three.Some patients who have MFS or BBE may notshow ataxia at the onset of neurological symp-toms and therefore acute ophthalmoparesisshould be diagnosed. This suggests that acuteophthalmoparesis without ataxia is a restrictedand mild condition of MFS or BBE.

IMMUNOLOGICAL EVIDENCE THAT MFS, GBS, BBE,AND ACUTE OPHTHALMOPARESIS FORM A

CONTINUOUS RANGE

For each condition, antecedent illness causedby upper respiratory infection was present in60% to 80% of the patients, and CSF albumi-nocytological dissociation in 25% to 75%. Thissuggests that a common autoimmune mech-anism functions in the pathogenesis of theseconditions.

Whereas anti-GQ1b IgG is an immunologi-cal marker of MFS and related disorders,3–5 8

anti-GM1 IgG autoantibody may be a serologi-cal marker of axonal GBS.19 33 Anti-GD1a IgGantibody is closely associated with the axonalform of GBS,20 but was not detected in typicalpatients with MFS who did not show limbweakness.3 4 34 C jejuni is a common antecedentagent in MFS,13 as well as in GBS,35 36 andsome patients who present as having MFSsubsequent to C jejuni enteritis then progress toGBS.37 38 A single strain of C jejuni has severallipopolysaccharides that bear epitopes com-mon to such gangliosides as GM1, GD1a, andGQ1b.39 40 Infection by a strain of C. jejuni mayinduce not only anti-GQ1b IgG, but anti-GM1or anti-GD1a IgG in some patients with MFS/GBS. Among our patients with MFS/GBS, Cjejuni actually was isolated from one withMFS/GBS who had anti-GQ1b and anti-GD1a IgG antibodies (case 4 of Ohtsuka etal41). We therefore compared the frequencies ofanti-GM1 or anti-GD1a IgG in MFS, MFS/GBS, and GBS. As expected, the frequency ofanti-GM1 or anti-GD1a IgG in MFS/GBS(35%) was between that in MFS (16%) andthat in GBS (50%). Moreover, the frequency ofanti-GM1 or anti-GD1a IgG in BBE/GBS(27%) was between that in BBE (8%) and thatin GBS (50%). In addition to the similarities inclinical presentation and share of anti-GQ1bIgG autoantibody, immunological results forthe overlapping cases show that MFS, GBS,and BBE are closely related, not distinct,autoimmune mediated disorders. The patientswith acute ophthalmoparesis had neither anti-GM1 nor anti-GD1a IgG. Serologically thisindicates that MFS or BBE is located betweenacute ophthalmoparesis and GBS.

RECOGNITION OF ANTI-GQ1b IgG ANTIBODY

SYNDROME AND ITS THERAPY

In this larger study, we confirmed clinically thatMFS, GBS, BBE, and acute ophthalmoparesisare closely related and form a continuous range(figure). This was supported by immunologicalfindings. We do not intend the term “anti-

Nosological relations between Miller Fisher syndrome, acute ophthalmoparesis, BickerstaV’sbrain stem encephalitis, and Guillain-Barré syndrome.

Acute opthalmoparesis

Miller Fisher syndrome

110

7

15

1211

8

31

Bickerstaff's brain stem encephalitis

Guillain-Barré syndrome

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GQ1b IgG antibody syndrome” to be used as aclinical diagnosis, but recognition of thissyndrome is useful for understanding theaetiological relations of MFS, GBS, BBE, andacute ophthalmoparesis. Moreover, establishedtreatments for GBS (plasmapheresis and intra-venous immunoglobulin) may be more readilyintroduced as treatments for BBE and acuteophthalmoparesis, as well as for MFS. Somepatients with BBE and acute ophthalmoparesishave responded favourably to plasmapheresisand intravenous immunoglobulin8 23 24 42 Re-cent studies by Buchwald et al43 and Plomp etal44 show that anti-GQ1b IgG, at least, is apathophysiological mediator of motor symp-toms in MFS and related disorders. This istheoretical evidence that removal of theautoantibody is eYcacious treatment for pa-tients with anti-GQ1b IgG.

This research was supported in part by grants in aid for Scien-tific Research (10780482 and 10557063 to NY) from the Min-istry of Education, Science, Culture, and Sports of Japan andthe Ryoichi Naito Foundation for Medical Research and aResearch Grant for Neuroimmunological Diseases from theMinistry of Health and Welfare of Japan.

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3 Chiba A, Kusunoki S, Shimizu T, et al. Serum IgG antibodyto ganglioside GQ1b is a possible marker of Miller Fishersyndrome. Ann Neurol 1992;31:677–9.

4 Yuki N, Sato S, Tsuji S, et al. Frequent presence ofanti-GQ1b antibody in Fisher’s syndrome. Neurology 1993;43:414–7.

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Anti-GQ1b IgG antibody syndrome 55

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immunological rangeAnti-GQ1b IgG antibody syndrome: clinical and

M Odaka, N Yuki and K Hirata

doi: 10.1136/jnnp.70.1.502001 70: 50-55 J Neurol Neurosurg Psychiatry 

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