clinical and immunological spectrum of the miller fisher syndrome

INVITED REVIEW ABSTRACT: The Miller Fisher syndrome (MFS), characterized by ataxia,areflexia, and ophthalmoplegia, was first recognized as a distinct clinicalentity in 1956. MFS is mostly an acute, self-limiting condition, but there isanecdotal evidence of benefit with immunotherapy. Pathological data remainscarce. MFS can be associated with infectious, autoimmune, and neoplasticdisorders. Radiological findings have suggested both central and peripheralinvolvement. The anti-GQ1b IgG antibody titer is most commonly elevated inMFS, but may also be increased in Guillain–Barre syndrome (GBS) andBickerstaff’s brainstem encephalitis (BBE). Molecular mimicry, particularly inrelation to antecedent Campylobacter jejuni and Hemophilus influenzaeinfections, is likely the predominant pathogenic mechanism, but the roles ofother biological factors remain to be established. Recent studies havedemonstrated the presence of neuromuscular transmission defects in asso-ciation with anti-GQ1b IgG antibody, both in vitro and in vivo. Collectivefindings from clinical, radiological, immunological, and electrophysiologicaltechniques have helped to define MFS, GBS, and BBE as major disorderswithin the proposed spectrum of anti-GQ1b IgG antibody syndrome.

Muscle Nerve 36: 615–627, 2007

CLINICAL AND IMMUNOLOGICAL SPECTRUMOF THE MILLER FISHER SYNDROME

Y. L. LO, MD

Department of Neurology, National Neuroscience Institute, Singapore General Hospital,Outram Road, 169608 Singapore

Accepted 4 May 2007

The Miller Fisher syndrome (MFS) was first de-scribed clinically in 1956.40 The original article hadpostulated it as an unusual variant of acute idio-pathic polyneuritis, implying a strong relation withthe Guillain–Barre syndrome (GBS). The classictriad consisted of ophthalmoplegia, ataxia, andareflexia in an acute setting, and was first recognizedby Collier in 1932.34

In this review, published information on all as-pects of MFS will be summarized and discussed,mostly in a chronological fashion, to provide a com-prehensive account of developments pertaining tothis condition. As such, origins of the proposed anti-GQ1b IgG antibody syndrome, comprising MFS,GBS, and Bickerstaff’s brainstem encephalitis(BBE), will also be apparent.

SEARCH STRATEGY AND CRITERIA

References for this review were identified bysearches of PubMed from 1971 to April 2006 withthe terms “Miller Fisher syndrome,” “Fisher syn-drome,” “Fisher’s syndrome,” “Guillain–Barre syn-drome,” “Bickerstaff’s brainstem encephalitis,” and“anti-GQ1b antibody.” Due to the extensiveness ofthis topic, prioritization was given to publicationsrelevant to MFS. Selective data on GBS were in-cluded. Case reports were selected based on origi-nality. Other materials were from the author’s ownfiles. Only articles in the English language were in-cluded.

DIAGNOSIS

For the clinician, a diagnostic approach in confront-ing the varied features comprising diplopia, dysar-thria, facial asymmetry, motor incoordination, sen-sory disturbances, and weakness due to long-tractinvolvement is most relevant. Unfortunately, increas-ing knowledge of MFS and related disorders fromantibody-specificity studies, in relation to clinical syn-dromes, have made discrete characterization diffi-cult. Various formes frustes and overlap syndromesare increasingly reported, which expand the under-

Available for Category 1 CME credit through the AANEM at www.aanem.org.

Abbreviations: BBE, Bickerstaff’s brainstem encephalitis; GBS, Guillain–Barre syndrome; MFS, Miller Fisher syndrome; MRI, magnetic resonanceimagingKey words: anti-GQ1b IgG antibody; Bickerstaff’s brainstem encephalitis;Guillain–Barre syndrome; Miller Fisher syndrome; reviewCorrespondence to: Y. L. Lo; e-mail: [email protected]

© 2007 Wiley Periodicals, Inc.Published online 26 July 2007 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.20835

Miller Fisher Syndrome MUSCLE & NERVE November 2007 615

standing of this clinical spectrum. A logical clinicalapproach would be to consider MFS, GBS, and BBEas separate initial categories and rationalize existingoverlapping features. Before the advent of anti-GQ1b IgG testing (Table 1), the diagnosis of theseconditions was largely clinical, assisted by imagingand electrophysiological studies.

In considering MFS as a disease entity, research-ers or clinicians may choose to characterize it fromseveral starting points: clinical features, antibodyprofile, infective triggers, or a combination of these.It is widely accepted that anti-GQ1b IgG antibody ispresent in well over 90% of MFS patients, and isabsent in normal subjects or disease controls.

CLINICAL FEATURES

The classic clinical triad originally described a com-bination of central and peripheral involvement. Thisled to constructive debates on the existence of asingle lesion site.

In the largest reported series,105 comprising 50consecutive MFS patients, strict entry criteria ofacute ophthalmoplegia, ataxia, and areflexia, with-out major limb weakness or other signs suggestingcentral nervous system involvement, were applied.Antecedent respiratory symptoms occurred in 76%and gastrointestinal symptoms in 4%. The medianinterval between infection onset and development ofneurological symptoms was 8 days. Overall, 89% hadelevated anti-GQ1b IgG antibodies. A median inter-val of 12–15 days was found between neurologicalonset and the beginning of recovery. By 6 months,all patients were free from ataxia and ophthalmople-gia. No deaths were reported. Table 2 summarizesthe neurological signs and symptoms in these pa-tients. Comparison made with another large seriesdid not reveal differences, suggesting fairly uniformclinical features.

Clinically, MFS is mostly a self-limiting condi-tion.105 However, cases progressing to respiratory

failure and requiring mechanical ventilation havebeen described,14 particularly in children.6,10,133

Other serious complications reported include co-ma,97 ballism,118 cardiomyopathy from dysautono-mia,124 lactic acidosis,150 and pain.79,100 Recurrenceof MFS,16,69,95,125,143,145,152 sometimes showing differ-ent phenotypes at different times, has been welldocumented.51

Ophthalmological and Cranial Nerve Features. Theclinical features of MFS are of great clinical interest,particularly the ophthalmological aspects. Apartfrom visual impairment from optic neuritis,22,23,33,160

other ophthalmological abnormalities include diver-gence paralysis,130 lid retraction, upper lid jerks, in-ternuclear ophthalmoplegia, convergence spasm,Parinaud’s syndrome, defective vestibulo-ocular re-flex,2 chronic ophthalmoplegia,134 areflexic mydria-sis, convergence failure,21,24 and acute angle clo-sure.159 Isolated abducens nerve palsy was suggestedto be a mild form of MFS in a recent study.159 Thefacial nerve was involved in 45.7% of patients in oneseries.12

Ataxia. The origin of ataxia in MFS is of profoundclinical interest. The original study by Fisher40 pro-

Table 2. Comparison of two large published clinical serieson MFS.

Mori et al.(n � 50)105

Lyu et al.(n � 32)93

Mean age NM 45 yearsMedian age 40 years NMGender Male

preponderanceNo genderdifference

Season Spring SpringUpper respiratory infection 76% 56%Acute gastroenteritis 4% 0%Median time to nadir 6 days 5.5 days

Clinical features (%)Pupillary abnormalities 42 NMPtosis 58 59Facial palsy 32 50Bulbar palsy 26 59Limb weakness 20 25Limb dysesthesia 24 34Superficial sensory loss 20 50Trigeminal dysfunction NM 16Abnormal vibratory and

deep sensation18 NM

Micturition disturbance 8 3

All patients had ataxia, areflexia, and ophthalmoplegia.No significant differences in clinical features were found between the twoseries (unpaired t-test, P � 0.3).NM, not mentioned.

Table 1. Clinical spectrum of the anti-GQ1b antibody syndrome.

Disorder Clinical featuresAnti-GQ1b antibody

frequency

MFS Ataxia, areflexia,ophthalmoplegia40

Up to 95%76

GBS Weakness, sensory loss,areflexia, cranialneuropathy164

Up to 26%22

BBE Ophthalmoplegia, ataxia,hypereflexia or disturbedconsciousness120

Up to 66%120

616 Miller Fisher Syndrome MUSCLE & NERVE November 2007

posed selective involvement of Ia-afferent neurons.Early case studies correlated abnormalities of Ia-afferent fibers with the severity of ataxia, suggestingthis process is indeed involved in its development.165

Ropper and Shahani138 suggested that disparity be-tween proprioceptive information from muscle spin-dles and kinesthetic information from joints may bea mechanism of ataxia, based on abnormalities ofperipheral nerves. Employing postural body swayanalysis, Kuwabara and colleagues82 concluded thatMFS patients have dysfunction of the proprioceptiveafferent system, and that sensory ataxia may becaused by selective involvement of muscle-spindleafferents.

Anti-GQ1b monoclonal antibody immunostain-ing of human dorsal root ganglion has been demon-strated, but its physiological significance remains un-certain.81 Direct staining of Ia afferents with anti-GQ1b IgG antibody has not been demonstrated todate.

In ataxic GBS, distal paresthesias, areflexia, andsensory ataxia have been documented. Some cases,however, showed features suggesting cerebellar-typeataxia. Ataxic GBS may progress to typical GBS,where limb weakness predominates. In a large seriesof 340 cases with anti-GQ1b IgG antibody positivity,6 cases were consistent with the ataxic form of GBS.Anti-GQ1b IgG antibody from these patients cross-reacted with GT1a, suggesting that autoantibodieswith the same fine specificity were seen in MFS andataxic GBS.175

In a large series of 445 patients with GBS, anti-GD1b IgG without cross-reactivity with other glyco-lipids was present in 9 cases, all with sensory distur-bance and 1 with cerebellar ataxia.102 Other GBScases reported subsequently had sensory ataxia andsimilarly elevated anti-GD1b IgG antibody.168,175 AsGD1b was found to localize to primary sensory neu-rons in humans, these reports seem to favor bothcerebellar and sensory involvement as causes for theataxia.

Immunological evidence of cerebellar involve-ment would be of interest for explaining the ataxiain MFS. A 1-year study using immunocytochemicalstaining of human cerebellum described selectivestaining of the molecular layer with sera from 3 MFSor GBS patients who had elevated IgG anti-GQ1bantibody levels.80 Western blot analysis also revealedincreased levels of anti-cerebellar antibodies in MFSpatients when compared with GBS patients orhealthy controls.60 These findings suggest the pres-ence of immunologically mediated cerebellar dys-function in MFS, but more studies are needed tofurther define the role of anti-GQ1b IgG antibody, as

well as the underlying immunological mechanism ofcerebellar dysfunction in MFS.

In summary, the issue of ataxia in MFS has notbeen fully explained. It is possible that the relativepredominance of anti-GQ1b or anti-GD1b IgG anti-bodies may contribute to the ataxia, but furtherstudies in large series will help to resolve these issues.

Areflexia. Areflexia is a clinical sign suggesting pe-ripheral nervous system involvement. It forms part ofthe clinical triad of MFS, and is an overlapping clin-ical feature with GBS. In the largest series of MFSreported to date, all patients demonstrated loss ofreflexes and, over a 4–6-month period of follow-up,two thirds still showed abnormally depressed tendonreflexes.105 The presence of areflexia corroborateselectrophysiological studies demonstrating periph-eral nerve dysfunction,66,67 including axonal neurop-athy41 and abnormal conduction in peripheral sen-sory fibers.47 These findings were very similar tothose seen in GBS.

CLINICAL ASSOCIATIONS

MFS with an immunological basis has been de-scribed in association with autoimmune and neoplas-tic conditions. It has been reported in conjunctionwith systemic lupus erythematosus,13,54 Hashimoto’sthyroiditis,132 Still’s disease,37 Hodgkin’s disease,139

leptomeningeal signet cell carcinomatosis,109 andlung carcinoma.35 Tacrolimus therapy has also beenassociated with MFS developing in a patient receiv-ing a cadaveric liver transplant.71 However, theseanecdotal reports do not in themselves qualify MFSas a paraneoplastic manifestation or rheumatologi-cal disorder.

EPIDEMIOLOGY

The annual incidence of MFS has been estimated at0.09 per 100,000 population and onset is most com-mon in spring. However, large epidemiological stud-ies on MFS remain scarce, and the majority of pub-lished data have been culled from studies on GBS.An incidence of MFS making up 25% of GBS pa-tients was recorded in a Japanese series published in2001.105 A retrospective 11-year hospital study in Tai-wan noted an unusually high percentage (18%) ofMFS among GBS patients, most commonly in win-ter.172 A separate 14-year retrospective review re-corded 7 MFS cases among 96 (7%) cases classifiedas GBS.25 This was in contrast to a prospective Italianstudy, which recorded 4 MFS cases from among 138GBS patients (3%).15 There is thus anecdotal evi-


dence to suggest a higher proportion of MFS amongGBS patients in the Far East. The exact reasonsremain speculative, but may be related to host fac-tors and genetic factors. In addition, uniform defi-nition of diagnostic criteria for MFS, as well as thosefor GBS and BBE, will enable future epidemiologicalstudies to estimate incidence more accurately.

Of the few reports addressing MFS in children,one study58 quoted MFS as being diagnosed in 2 of23 (9%) GBS cases. Both patients recovered with noresidual deficits.

PATHOLOGY

Few reports of autopsies on MFS patients have beenpublished, reflecting the mostly self-limiting clinicalcourse. Two autopsy reports failed to find a centralnervous system lesion129,137; one described demyeli-nating peripheral neuropathy, suggesting that MFSfalls within the spectrum of acute inflammatory poly-neuropathy,133 similar to GBS. Histological examina-tion has demonstrated segmental demyelination andaxonal swelling in peripheral and oculomotornerves, in addition to mild chromatolytic changesand pyknosis of the midbrain in a 64-year-old womanwith recurrent MFS.9 A 1992 review documented 6autopsied patients: 3 showed inflammatory brain-stem lesions and 2 had demyelination of the cranialnerves.12 Hence, the evidence of central pathology islimited and has been derived mostly from radiolog-ical or electrophysiological studies.

RADIOLOGICAL FINDINGS

The advent of magnetic resonance imaging (MRI)has contributed greatly to our understanding ofMFS. To provide a balanced comparison of centraland peripheral involvement, I have arbitrarily in-cluded cranial nerve findings as peripheral lesions.

Imaging is unremarkable in most cases of MFS.The earliest reports of MRI findings associated withMFS showed lesions in the brainstem42,158 and IIInerve nucleus on T2-weighted sequences,53 provid-ing evidence supporting central involvement. Otherreports have described spinocerebellar tract lesionsin the lower medulla,162 and lesions in the midbrain,pons, and middle cerebellar peduncle.32 This maysuggest an immune-mediated breach of the blood–brain barrier, as demonstrated in previous cerebro-spinal fluid studies.149

Peripheral lesions reported in MFS included le-sions in the lumbosacral roots,128 cauda equina, pos-terior column of the spinal cord,61 III or IV cranialnerves,57,107,157 and dorsal root ganglia.84

In comparison to typical GBS, there are abun-dant reports of central lesions on MRI. With im-proved imaging methods, it is likely that more le-sions will be reported, lending support to themultifocal nature of this condition.

ELECTROPHYSIOLOGICAL ASPECTS

Early studies employing nerve conduction studiesdemonstrated peripheral sensory conduction abnor-malities.47,67 Subsequent studies, including use ofthe blink reflex,142 highlighted axonal neuropathicchanges and cranial motor dysfunction,41,144 suggest-ing some differences from the electrophysiologicalfeatures of GBS. The presence of evoked potentialabnormalities (visual, auditory, somatosensory) hasprovided electrophysiological evidence of combinedcentral and peripheral lesions in this condi-tion.46,160,169 Four MFS patients progressing to severetetraparesis showed reduced amplitudes of com-pound muscle action potentials, additionally sug-gesting electrophysiological differences from classicdemyelinating GBS.70 Quantitative cardiovascularautonomic function tests may be subclinically abnor-mal in both the parasympathetic and sympatheticcomponents.94

Electroencephalographic findings were normalin all three patients in one adult series,66 whereastwo case reports in the pediatric age group demon-strated slowing of background rhythm. Abnormali-ties appeared to be mild and non-specific inMFS.10,97

The increasing awareness of combined centraland peripheral involvement in anti-GQ1b IgG anti-body–positive MFS has prompted further investiga-tion into this issue.121 Using serial transcranial mag-netic stimulation, the prolonged subclinical centralmotor conduction time, a reflection of corticospinaldysfunction, was shown to reduce and normalize intandem with clinical recovery in anti-GQ1b IgG an-tibody–positive MFS.91 A reversible corticobulbarmotor conduction time abnormality was also dem-onstrated in one MFS patient exhibiting dysarthria.92

These findings highlight the presence of clinical andsubclinical functional lesions in anti-GQ1b IgG anti-body–positive classic MFS patients or patients withMFS features, in addition to other clinical signs. Thefindings also strengthen the relationship betweenMFS and the related disorder of BBE, where uppermotor neuron signs may coexist with ophthalmople-gia, ataxia, or an alteration of consciousness.

The role of anti-GQ1b IgG antibody in centralnervous system lesions, as demonstrated by electro-physiological and radiological studies, is uncertain.


Indeed, in BBE, where upper motor neuron–typelesions and sensorium changes are most frequentlyencountered, up to 66% of patients have this anti-body. Much work remains to be done to uncover itsactions at different levels of the nervous system. Inaddition, it remains to be determined whether therole of anti-GQ1b IgG antibody in the central ner-vous system is similar to that in the peripheral ner-vous system. How significant is the involvement ofother antibodies? These are intriguing questions,and their answers may provide further insight intothis group of disorders.

There is evidence that anti-GQ1b IgG antibodieshave pathogenic effects at the neuromuscular junc-tion in vitro. Using single-fiber electromyography,patients with acute ophthalmoparesis and elevatedanti-GQ1b IgG antibody were shown to have abnor-mal jitters, which improved with clinical recovery,86

providing the first reported evidence of neuromus-cular transmission defect in patients with MFS. Sim-ilar observations in an anti-GQ1b IgG antibody–neg-ative patient were made by separate investigators,141

suggesting that other antibodies may be involved.Employing high-frequency repetitive nerve stimula-tion,87–89 a presynaptic neuromuscular transmissiondefect was demonstrated in anti-GQ1b IgG anti-body–positive MFS patients90 up to 3 months after

clinical presentation. This corroborates in vitro find-ings of presynaptic structural derangements occur-ring in the nerve terminal,50 as opposed to a tran-sient nerve-blocking phenomena. Such an effect wasnot seen in antibody-negative cases, thus providingfurther evidence of anti-GQ1b IgG antibody–relatedpresynaptic dysfunction in MFS patients. Most re-cently, using abnormal single-fiber electromyogra-phy of the extensor digitorium communis muscle ofan MFS patient, findings further validated the previ-ously mentioned electrophysiological studies.83

Although the electrophysiological studies may benon-specific and correlational, the findings provideimportant functional information linking immuno-logical and clinical data in MFS (Fig. 1).

TREATMENT

It is relevant to note that the half-lives of IgM andIgA are 5 and 6 days, respectively. The half-life ofIgG, by comparison, is 21 days. Plasmapheresis iseffective at shortening the clinical course of GBS,which reaches a nadir by 8–9 days. This suggests thatthe presence of IgG is the predominant factor in thedevelopment of GBS. The median time to nadir inMFS is 5–6 days,105 indicating a somewhat shortertime to maximal clinical deficit.

FIGURE 1. Summary of possible protean effects of anti-GQ1b IgG antibody as evaluated by various electrophysiological techniques inMFS patients.


There are no randomized, double-blind, placebo-controlled trials pertaining to the treatment of MFS.This again is likely related to its self-limiting clinicalcourse and low incidence. Nonetheless, immuno-modulatory treatments similar to those used in GBShave been reported anecdotally. In a large series of 50consecutive cases, no beneficial effect was shown inpatients who received plasmapheresis compared withthose who received no immunotherapy.104

The use of plasmapheresis85,96,171 with success hasmostly been described in case reports, as was the useof intravenous immunoglobulin.181 However, the lat-ter should be used judiciously; a case of cerebralinfarction was reported during treatment of an MFSpatient,161 and posterior reversible encephalopathyhas also occurred.108

Employment of immunoadsorption in a trypto-phan-immobilized column was effective in reducinganti-GQ1b IgG antibody titers from patients’ se-ra.123,180 Willison et al. provided in vitro rationale forimmunoadsorption plasma exchange by showingthat synthetic disialygalactose immunoadsorbentsdeplete anti-GQ1b IgG antibodies from MFS-associ-ated human sera.166 This provides the impetus formore research into developing immunotherapieswith greater antibody specificity and binding effi-cacy.

Future therapeutic directions could be focusedon use of novel agents acting at various levels of theimmunological cascade or at motor nerve terminals.

Although MFS and GBS are related disorders,they have different clinical courses and antibodyprofiles. The present immunomodulatory treat-ments of MFS are largely translated from experi-ences with GBS. To establish convincingly the effi-cacy of these treatments would require large,prospective clinical trials.

At present, clinical discretion should be employedas to when treatment can be instituted in the absenceof established guidelines. MFS is self-limiting, but it isreasonable to consider treatment in cases with rapidprogression of limb, bulbar, or respiratory weakness.

CAMPYLOBACTER AND OTHER INFECTIONS

Like GBS, MFS has been reported to follow infec-tions. Molecular mimicry4,62 has been shown to bethe likely mechanism by which infective agents trig-ger an immunological reaction.

MFS has been associated with Q fever,38 and withinfection with Mycoplasma pneumoniae,99 human im-munodeficiency virus,7 Campylobacter jejuni,3,31,43,110

Epstein–Barr virus,146 Hemophilus influenzae,75 Pastu-ella multocida,11 Helicobacter pylori,30 aspergillus,39

Streptococcus aureus, cytomegalovirus, varicella-zostervirus, and mumps virus.156 However, a large prospec-tive case–control serological study has shown thatassociated infective agents remain unknown in themajority of cases.72

Of the multiple antecedent infections reportedin MFS, C. jejuni infection, as in GBS, has been themost well studied.78 In a large, prospective case–control study, comprising 96 GBS and 7 MFS pa-tients,135 evidence of C. jejuni infection was presentin 2 of the 7 MFS patients, and was associated withaxonal degeneration, slow recovery, and residual dis-ability. C. jejuni GBS is commonly associated withformation of IgG antibodies against GM1, GM1b,GD1a, or GalNAc-GD1a.177

Jacobs et al.62 isolated C. jejuni from 3 MFS pa-tients, all with high anti-GQ1b IgG antibody titers,and demonstrated cross-reactivity of these antibodieswith surface epitopes of C. jejuni strains by enzyme-linked immunosorbent assay inhibition techniques.The findings support the hypothesis of molecularmimicry between bacteria and nerve tissue. In an-other series, C. jejuni was isolated from 3 MFS pa-tients with anti-GQ1b IgG, which cross-reacted withsialidase-sensitive epitopes in the lipopolysaccharidefractions, supporting the hypothesis that anti-GQ1bIgG antibodies are induced during preceding C. je-juni infection.64 There was further evidence to sug-gest that GBS and MFS induced long-lasting elevatedtiters of IgG1 and IgG3 antibodies, as compared withIgG2 in normal controls, suggesting that specificityof antibody isotype may be determined by precedingC. jejuni infection.63 Schwerer et al.147 showed that,in MFS following respiratory infection, IgG3 was themajor antibody detected, in contrast to IgA,76 IgM,or IgG2, following gastrointestinal infections. A Jap-anese study determined that Penner’s serotype 2 ofC. jejuni causing enteritis was particularly associatedwith MFS,122 in contrast to Penner’s serotype 19,which mainly triggered GBS.155,173

Recent research on C. jejuni has focused on itsgenetic aspects. A Campylobacter gene (cstII) wasfound to be associated with immune-mediated neu-ropathy by the demonstration that cstII sialic acidtransferase was a crucial determinant in the synthesisof GQ1b epitope.163 Oligoclonal expansions of Tcells bearing particular types of T-cell receptor Vbeta and V delta genes frequently occur in GBS/MFS, suggesting a role of T-cell mediation.77 Em-ploying Campylobacter knockout mutants and associ-ation studies of lipo-oligosaccharide biosynthesisgene locus with expression of ganglioside-mimickingstructures, it was shown that specific bacterial genesare crucial for induction of anti-ganglioside antibod-


ies.44 Koga et al.74 demonstrated that patients in-fected with C. jejuni Asn51 polymorphism were moreoften positive for anti-GQ1b IgG antibody andshowed ataxia. In contrast, patients with C. jejuniThr51 were more frequently positive for anti-GM1and anti-GD1a IgG antibody, and these patientsmanifested weakness predominantly. This findingsuggested that genetic polymorphism of C. jejunidetermines autoantibody reactivity and clinical pre-sentation in GBS/MFS.

MOLECULAR MIMICRY

Molecular mimicry represents a major pathogenicmechanism, and understanding this process mayhave important implications for treatment.

Studies of molecular mimicry in MFS, in relationto anti-GQ1b IgG antibody, have been carried outwith strategies similar to those in GBS. Yuki et al.175

isolated two strains of C. jejuni from patients withanti-GQ1b IgG antibody. The monoclonal antibod-ies cloned reacted with both lipopolysaccharide frac-tions, implying that the lipopolysaccharide of C. je-juni bears GQ1b epitopes, and mimicry betweenGQ1b and C. jejuni lipopolysaccharide has occurred.Salloway et al.140 isolated lipopolysaccharide from C.jejuni (serotype O:10) from an MFS patient and dem-onstrated that its terminal trisaccharide epitope con-sisted of two molecules of sialic acid linked to galac-tose, reflecting the terminal region of human GD3ganglioside, which is also present in the lipopolysac-charide of neuropathic O:19 strains of C. jejuni. Thissuggests a possible role in molecular mimicry of thistrisaccharide. In a separate study,8 the lipopolysac-charide of the OH 4384 strain of C. jejuni containedGM1 and GD1a-like epitopes. Immunization of micewith lipopolysaccharides of this strain inducedmonoclonal antibodies with GQ1b reactivity. It wasfurther demonstrated4 that one of the four rabbitsinjected with lipopolysaccharides from two MFS-related C. jejuni strains produced anti-GQ1b IgGantibody. These findings further attest to the pres-ence of molecular mimicry in the autoimmune de-velopment of MFS preceded by C. jejuni infection.However, animal experiments have demonstrateddifferences in the specificity of anti-ganglioside anti-body responses between rabbits immunized with li-popolysaccharides from the same Campylobacterstrain, suggesting that lipopolysaccharides onlypartly determine anti-ganglioside antibody specific-ity. Other strain-specific and host-related factors maycontribute.4

Koga et al.75 found serological evidence of H.influenzae in 7% of 70 consecutive MFS patients, all

with antecedent respiratory tract infection. Anti-GT1a IgG antibody cross-reactivity with GQ1b waspresent in all the patients. Their anti-GQ1b mono-clonal antibodies bound to the lipopolysaccharidesextracted from H. influenzae samples, suggesting thatthis lipopolysaccharide contained GT1a epitope.Molecular mimicry may thus be the likely mecha-nism for development of MFS after H. influenzaeinfection. Recent studies have suggested, however,that H. influenzae isolation may not always be indic-ative of its causal role in MFS/GBS, and testing forother infections should be undertaken during clini-cal management.73 There is also evidence to suggestthat antibodies to the vacuolating cytotoxin of Heli-cobacter pylori show homology with membrane ion-transport proteins, suggesting a role in MFS patho-genesis.30 Research into GBS/MFS has extended tocellular lipidomics, where differential effects onphospholipids activity with anti-GM1 vs. anti-GQ1bantibody was demonstrated in patients’ sera.55

In summary, collective evidence from bacterio-logical and immunological studies strongly supportsmolecular mimicry as the major pathogenic mecha-nism, but the presence of other genetic and hostdeterminants is becoming apparent. With advancesin biochemical and cellular technology, there will besignificant new developments in this field of diseasepathogenesis.

ANTI-GQ1b IgG ANTIBODY

Gangliosides are glycosphingolipids that contain asialic acid residue of N-acetylneuraminic acid at-tached to the terminal galactose of an oligosaccha-ride core. They play a role in plasma membrane andcell functions. The hydrophilic carbohydrate struc-ture is exposed extracellularly, and is capable ofacting as an autoantibody target. The gangliosideGQ1b (Fig. 2) is abundant in cranial nerves supply-ing extraocular muscles and the presynaptic neuro-muscular junction, which is devoid of a blood–nervebarrier. This may render it vulnerable to autoim-mune attack. The corresponding antibody, anti-GQ1b, is IgG in class and its titer rapidly decreaseswith clinical resolution of MFS.

Anti-GQ1b antibody is well known to be associ-ated with MFS.126 Anti-GQ1b IgG antibody titerspeak at clinical presentation and decline rapidly dur-ing the course of recovery. However, some studieshave measured its titer over the first 2 weeks afteronset and found that anti-GQ1b IgG antibody activ-ity reflected clinical severity scores, especially oph-thalmoplegia.45,103 Anti-GQ1b IgG antibody fre-quently cross-reacts with ganglioside GT1a, as well as


GD3 and GD1b.179 Such demonstrated specificitycan be useful to the managing clinician, who canconsider testing for the presence of anti-GQ1b IgGantibody activity or antibodies to these relatedepitopes, as markers for identification of MFS or itsformes frustes. Longitudinal testing has shown thatanti–C. jejuni IgG and IgA antibody titers parallelthat of anti-ganglioside antibodies, indicating that C.jejuni infection triggers antibody production.116 Anti-GQ1b IgG antibody positivity, occurring in variousfrequencies, has been reported in MFS, GBS, andBBE.5,117 From the clinical standpoint, anti-GQ1bIgG antibody positivity is most highly correlated withophthalmoplegia,154 but an association with ataxiafrom binding to dorsal root ganglia81 has been doc-umented. Associations with pure ataxia36,106 or iso-lated ophthalmoplegia174 have also been described.Anti-GQ1b IgG antibody testing was found to bestatistically superior to cerebrospinal fluid examina-tion for MFS diagnosis in the first 3 weeks of presen-tation.111 These clinical studies point to the presenceof a range of manifestations, from isolated ophthal-moplegia to the classic triad of MFS, in anti-GQ1bIgG antibody–positive patients.

It should be noted that the notion of an anti-GQ1b IgG antibody syndrome was not intended as anew diagnosis, but rather as recognition of a closeetiological relation between MFS, GBS, and BBE.117

IMMUNOLOGICAL ASPECTS

Although MFS, like GBS, is an immune-mediatedcondition, it remains uncertain as to how antibodymediation can be translated to motor manifesta-tions. Increased activity of anti-GQ1b IgG antibodywas shown to be present in most cases of MFS,29,167

and anti-GQ1b mouse monoclonal antibody immu-nostained the paranodal region of extramedullaryIII, IV, and VI cranial nerves. The paranodal regionsare important for nerve impulse conduction. It wasalso demonstrated with anti-GQ1b monoclonal anti-body that staining of GQ1b occurred specifically andwas densely localized in the paranodal myelin sheathof cranial nerves III, IV, and VI, but not in othercentral nervous system structures.27 Cranial nerve IIIwas shown to contain a larger amount of GQ1b thanspinal nerves roots, suggesting a role of anti-GQ1bIgG antibody in ocular manifestations of MFS.28

The motor effects of anti-GQ1b IgG antibodyremain poorly understood. Roberts et al.136 first in-vestigated the effects of anti-GQ1b IgG antibody–positive sera on mouse phrenic nerve–diaphragmpreparations, and showed that miniature endplatepotential frequencies increase, decline rapidly, andthen cease after nerve stimulation, suggesting failureof neuromuscular transmission from nerve terminalsin MFS. Patch-clamp techniques have shown thatreversible presynaptic neurotransmitter releaseblockade may contribute to muscle weakness inMFS,18 possibly due to the interference of calciuminflow or proteins in the exocytic apparatus.19

Further studies using similar methods followed,showing that anti-GQ1b IgG antibody binds to theneuromuscular junction, inducing a massive quantalrelease of acetylcholine, resembling effects of theneurotoxin alpha-latrotoxin. Experiments with com-plement-deficient sera suggested that anti-GQ1b IgGantibody acts in conjunction with activated comple-ment in the alternate pathways.20,131 It was subse-quently shown that circulating IgG antibodies inMFS could induce neuromuscular blockade at thepresynaptic and postsynaptic levels.17 Using immu-nofluorescence, electron microscopy, and micro-electrode recording, complement-mediated ultra-structural axon terminal and perisynaptic Schwann-cell destruction were demonstrated.49,115

These findings have led to studies on interven-tion. Intravenous immunoglobulin is commonlyused in the treatment of many immune-mediateddiseases, but the underlying mechanisms of actionare not well understood. It inhibits binding of anti-GQ1b IgG antibody to GQ1b and prevents comple-ment activation in ex vivo mouse models.65 Calpain

FIGURE 2. Molecular structure of ganglioside GQ1b, depictingthe ceramide portion within the plasma membrane, and the car-bohydrate structures exposed to extracellular fluid. Shaded: N-acetylneuraminic acid; grid: galactose; dots: N-acetylgalac-tosamine; lines: N-acetylglucosamine.


inhibitors may limit calcium influx and have beendemonstrated to reduce ultrastructural nerve termi-nal damage in mouse hemidiaphragm treated withanti-GQ1b IgG antibody, complement, or alpha-lat-rotoxin.114 Most recently, use of AP7070 (Microco-cept), a complement activation inhibitor, was shownto prevent the membrane attack complex cascadeformation both in vitro and in vivo,48 suggesting arole for nerve terminal neuroprotection in GBS orMFS. It remains to be seen whether these novelfindings can be translated to human trials in thetreatment of MFS and its related disorders.

Apart from anti-GQ1b, other antibodies associ-ated with development of MFS include anti-GT1a,48,59,113,151,175 anti-LM1,52,170 and anti-GD3,178

but anti-GM1 antibody titer elevation seems uncom-mon.98 Anti-GQ1b IgG antibody in MFS shows ex-ceptionally high cross-reactivity with gangliosideGT1a,148 but anti-GT1a antibody without GQ1b re-activity is less commonly observed. In particular, theataxic form of GBS has anti-GT1a as a commonantibody.176 Ataxic GBS has also been reported to beassociated with anti-GM1b and anti–GalNacAc-GD1aIgG antibodies.119 Cross-reaction of anti-GQ1b IgGwith GD1b was particularly evident in MFS patientswith impaired proprioception.153 Detection of anti-ganglioside antibody by agglutination assay may beas useful a rapid method as enzyme-linked immu-nosorbent assay.1 Although testing for anti-GQ1bIgG antibody is significant, recent studies have high-lighted the clinical importance of ganglioside com-plexes by showing that anti–GQ1b/GM1-positiveMFS patients were less likely to develop sensory dis-turbances.68

A study of anti-GQ1b IgG antibody–positive seraof MFS and GBS patients did not reveal any associ-ation of human leukocyte antigen types with immu-noresponse of anti-GQ1b IgG antibody.26 Elevatedlevels of interferon-gamma and T-helper 1 werefound,56 in keeping with other studies suggestingT-cell mediation in MFS pathogenesis.77 Reducedcerebrospinal fluid levels of hypocretin-1 were foundin 5 of 12 (42%) MFS patients. As hypocretin-1 isknown to be associated with sleep–wake cycles, fur-ther studies will help elucidate whether such patientshave disturbances in this physiological process.112

In summary, the pathogenesis of MFS is moststrongly associated with anti-GQ1b IgG antibody,and research into its treatment has been directed atthe effects of this antibody. However, it has movedbeyond this area, and downstream processes in theimmunological cascade may emerge as promisingtargets for future therapeutic intervention strategies.It can be speculated that research findings in this

direction may also have relevance for other post-infectious immunologically mediated medical condi-tions.

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clinical and immunological spectrum of the miller fisher syndrome

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