differences in membrane properties of axonal and demyelinating guillain-barré syndromes

Differences in Membrane Propertiesof Axonal and Demyelinating

Guillain-Barre SyndromesSatoshi Kuwabara, MD,1 Kazue Ogawara, MD,1 Jia-Ying Sung, MD,1 Masahiro Mori, MD,1

Kazuaki Kanai, MD,1 Takamichi Hattori, MD,1 Nobuhiro Yuki, MD,2 Cindy S.-Y. Lin, BE, MEngSc,3

David Burke, MD, DSc,3 and Hugh Bostock, PhD, FRS4

Guillain-Barre syndrome is classified into acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinat-ing polyneuropathy (AIDP) by electrodiagnostic and pathological criteria. In AMAN, the immune attack appears directedagainst the axolemma and nodes of Ranvier. Threshold tracking was used to measure indices of axonal excitability(refractoriness, supernormality, and threshold electrotonus) for median nerve axons at the wrist of patients with AMAN(n � 10) and AIDP (n � 8). Refractoriness (the increase in threshold current during the relative refractory period) wasgreatly increased in AMAN patients, but the abruptness of the threshold increases at short interstimulus intervals indi-cated conduction failure distal to the stimulation (ie, an increased refractory period of transmission). During the 4 weekperiod from onset, the high refractoriness returned toward normal, and the amplitude of the compound muscle actionpotential increased, consistent with improvement in the safety margin for impulse transmission in the distal nerve. Incontrast, refractoriness was normal in AIDP, even though there was marked prolongation of distal latencies. Supernor-mality and threshold electrotonus were normal in both groups of patients, suggesting that, at the wrist, membranepotential was normal and pathology was relatively minor. These results support the view that the predominantly distaltargets of immune attack are different for AMAN and AIDP. Possible mechanisms for the reduced safety factor in AMANare discussed.

Ann Neurol 2002;52:180–187

Guillain-Barre syndrome (GBS) is classified into demy-elinating and axonal categories by clinical, electrophysi-ological, and pathological criteria.1–4 In North Americaand Europe, the usual form of GBS is acute inflamma-tory demyelinating polyneuropathy (AIDP).5–7 In con-trast, a considerable number of GBS patients have acutemotor axonal neuropathy (AMAN) in China3 and Ja-pan.8,9 Autopsy studies of AMAN patients have foundextensive axonal degeneration of motor fibers,2 but mostAMAN patients recover well10 or even faster than pa-tients with AIDP.11 A likely interpretation for the quickrecovery is immune-mediated reversible effects on theaxolemma.8,10 In AMAN, previous electrodiagnosticstudies have shown that both quick resolution of con-duction block in the distal nerve terminals8 and at thecommon entrapment sites12 and the time course of this

recovery are different from those in AIDP patients.The mechanisms for conduction block in AMAN areunknown, but blockage of Na� channels has been pos-tulated as a possible pathophysiology in such disor-ders.10–13

High titers of serum anti–GM1 antibodies are foundin 10 to 42% of patients with GBS,3,9,14–16 butwhether this antibody plays a role in the pathophysiol-ogy of axonal dysfunction is a matter of controversy.Passive transfer of anti–GM1 antibodies to animalnerves has been shown to cause nerve conduction blockin some studies,17 but not in others.18 Similarly, incu-bation of isolated nerve preparations in vitro with anti–GM1 antibodies has decreased Na� currents or pro-duced conduction block in some studies,19–21 but notin others.22

From the 1Department of Neurology, Chiba University School ofMedicine, Chiba; 2Department of Neurology, Dokkyo UniversitySchool of Medicine, Tochigi, Japan; 3Prince of Wales Medical Re-search Institute, University of New South Wales and College ofHealth Sciences, University of Sydney, Australia; and 4Sobell De-partment of Neurophysiology, Institute of Neurology, QueenSquare, London, United Kingdom.

Received Mar 1, 2002, and in revised form Apr 5. Accepted forpublication Apr 6.

Published online Jun 21, 2002, in Wiley InterScience(www.interscience.wiley.com). DOI: 10.1002/ana.10275

Address correspondence to Dr Kuwabara, Department of Neurol-ogy, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: [email protected]

180 © 2002 Wiley-Liss, Inc.

In the 1990s, the threshold tracking technique wasdeveloped to measure several indices of axonal excitabil-ity (such as refractoriness, supernormality, late subnor-mality, threshold electrotonus, and strength-durationproperties), noninvasively in human subjects.23–27 Theseindices depend on the biophysical properties of the ax-onal membrane at the site of stimulation and can pro-vide an indirect insight into Na� or K� channel func-tion.23 We have used this technique in the hope that itmight clarify the mechanism of conduction failure inAMAN, and the differences between AMAN and AIDP.

Subjects and MethodsSubjectsEighteen consecutive GBS patients (15 men and 3 women)were studied (Table). Their condition fulfilled the clinicalcriteria for GBS,28 and their mean age was 42 years (range,17–72 years). The first electrodiagnostic studies were per-formed within 3 weeks of the onset. Thirteen of the patientswere treated with intravenous immunoglobulin infusions(n � 11) or plasmapheresis (n � 2), and pretreatment serumsamples taken during the first 10 days after onset werestored.

For threshold-tracking studies, control data were obtainedfrom 37 healthy subjects with mean age of 42 years (range,24–72 years). Patients with chronic inflammatory demyeli-nating polyneuropathy (n � 15), diabetes mellitus (n � 23),and amyotrophic lateral sclerosis (n � 22) served as neuro-logical controls. All subjects gave informed consent, and thestudy had the approval of the ethical committee of ChibaUniversity School of Medicine.

Conventional Electrodiagnostic StudiesNerve conduction studies were performed using conventionalprocedures. Motor studies were made on the median, ulnar,tibial, and peroneal nerves. Sensory nerve conduction studieswere performed to antidromic stimulation of the mediannerve. Patients were classified as having AIDP or AMAN onthe basis of the electrodiagnostic criteria of Ho and col-leagues.3

Multiple Excitability Measures UsingThreshold TrackingIn the threshold-tracking studies, the current required toproduce a compound muscle action potential (CMAP) thatwas 40% of maximum was determined with a computer pro-gram (QTRAC version 4.3 with multiple excitability proto-col TRONDHM; Institute of Neurology, London) as de-scribed elsewhere.23–27 The current required to produce aspecified CMAP size (40% of maximum) is referred to as the“threshold” for that CMAP size. The CMAP was recordedfrom the abductor pollicis brevis. For median nerve stimula-tion, the active electrode was placed over the nerve at thewrist, and the remote electrode was placed 10cm proximalover forearm muscle. Skin temperature near the stimulus sitewas maintained above 32.0°C.

The stimulus-response curves were measured using teststimuli of duration 0.2 and 1.0 milliseconds. From thesecurves, strength-duration time constant (�SD) was calculatedusing the following formula27,29:

�SD � 0.2�I0.2 � I1.0�/�I1.0 � 0.2I0.2�

where I0.2 and I1.0 are the threshold currents using test stim-uli of 0.2- and 1.0-millisecond duration, respectively. From

Table. Clinical Profiles of Patients with Guillain-Barre Syndrome

Patient No. Age (yr)/GenderCranial Nerve

PalsySensory

LossHughesGradea

Antiganglioside IgGAntibody Against

Acute motor axonal neuropathy1 22/M No No 3 GM1b, GalNAc-GD1a2 17/M No No 4 GM1b, GalNAc-GD1a3 48/M No No 2 GM1, GalNAc-GD1a4 35/M No No 3 GalNAc-GD1a5 27/M No No 2 GM1b, GalNAc-GD1a6 32/F No No 2 GM1b7 17/M Facial No 5 GM1, GM1b, GalNAc-GD1a8 26/M No No 4 GM1, GM1b9 34/M No No 210 24/M No No 2 GM1, GM1b

Acute inflammatory demyelinating polyneuropathy1 72/F Facial, bulbar Yes 42 70/M Facial Yes 43 56/F No Yes 34 57/M No Yes 35 71/M Facial Yes 26 59/M Facial, bulbar Yes 47 56/M No Yes 28 36/M Facial Yes 3

aAt the peak. 2; able to walk 5 meters without aids; 3; able to walk 5m with aids; 4, unable to walk; 5, requiring assisted ventilation.

Kuwabara et al: Axonal/Demyelinating GBS 181

the stimulus-response curves, the currents required to pro-duce CMAPs of 10 to 90% of the maximal CMAP wereused to calculate �SD for CMAPs of different sizes.24

To measure the recovery of axonal excitability after a sin-gle supramaximal stimulus (ie, the “recovery cycle”), we de-livered test stimuli at different intervals after the condition-ing stimulus. The conditioning stimulus was supramaximal,and the test stimulus tracked the threshold for a 40%CMAP. Conditioning-test intervals were systematicallychanged from 200 to 2 milliseconds. In threshold electroto-nus studies, membrane potential was altered using subthresh-old polarizing currents which were 40% of the uncondi-tioned threshold. Depolarizing and hyperpolarizing currentswere used, each lasting 100 milliseconds, and their effects onthe threshold for the test CMAP were measured before, dur-ing, and after the 100-millisecond current. For statisticalanalysis, differences in medians were tested with the Mann–Whitney U test, and a cross-correlation was tested with anal-ysis of variance, using Statistica for Windows 98 software.

Antiganglioside Antibody AssaysSera from the patients were tested for the presence of IgMand IgG antibodies to GM1, GM1b, GD1a, GalNAc-GD1a,and GQ1b by enzyme-linked immunosorbent assay as de-scribed elsewhere.30,31 Serum was considered positive whenthe titer was a ratio of 1 to 500 or more.

ResultsClinical Features and ElectrodiagnosisThe table shows clinical profiles of patients with GBS.Based on electrodiagnostic criteria, a diagnosis ofAMAN (n � 10) or AIDP (n � 8) was made for 18patients. Mean age was 28 years (range, 17–48 years)for the AMAN group and 59 years (36–72 years) forthe AIDP group (p � 0.01). Only one AMAN patienthad cranial and sensory nerve involvement, whereas allAIDP patients had sensory disturbances, and five hadfacial palsy. Clinical disabilities evaluated by theHughes grading scale were similar for the AMANgroup (median, 3.0; range, 2.0–5.0) and AIDP group(median, 3.0; range, 2.0–4.0).

In median motor conduction studies, the mean dis-tal latency was 4.3 milliseconds (range, 3.8–4.8 milli-seconds) in AMAN patients, which was slightly longerthan that of normal subjects (mean, 3.4 milliseconds;range, 3.1–4.2 milliseconds; p � 0.05). AIDP patientshad a much longer distal latency (mean, 8.7 millisec-onds; range, 5.9–16.3 milliseconds) than AMAN pa-tients and normal subjects (p � 0.0001). CMAP am-plitudes were significantly lower in patients withAMAN or AIDP than in normal subjects (p � 0.001).The mean amplitude of the negative peak of the distalCMAP was 3.9mV (range, 2.1–5.7mV) in AMAN pa-tients and 2.5mV (range, 0.2–5.5mV) in AIDP pa-tients (p � 0.13). The mean motor conduction veloc-ity was 53m/sec (range, 40–64m/sec) in AMAN

patients, and 40m/sec (32–50m/sec) in AIDP patients(p � 0.001). Median sensory nerve conduction studieswere normal in AMAN patients, whereas AIDP pa-tients had absent (n � 3) or slowed (n � 7) sensorypotentials. Nine of the 10 AMAN patients had IgGantibodies against ganglioside GM1, GM1b, GD1a, orGalNAc-GD1a, whereas none of the AIDP patientshad any of the tested antibodies (Table).

Multiple Excitability Measurements inNormal SubjectsBecause AMAN patients were significantly youngerthat AIDP patients, we looked for age-related changesin normal subjects. The 37 subjects were divided intotwo groups, young (aged 20–44 years; n � 20) andold (aged 45–80 years; n � 17). Comparison of thefindings between the two groups showed less supernor-mality for older subjects (mean � standard deviation,�18.9 � 8.9%) than for younger subjects (�27.9 �6.1%; p � 0.04), but the other indices were similar.Therefore in the analyses of supernormality, AMANpatients were compared with younger controls, andAIDP patients were compared with older controls.Other parameters were compared between the patientsand all 37 normal subjects.

Stimulus-response Curves and Strength-duration PropertiesIn the stimulus-response curves, threshold currentswere larger in the patients with AMAN or AIDP thanin the normal subjects (Fig 1; p � 0.01 for 50%CMAP), and the spread of thresholds was greater inthe patients than in controls. �SD for 50% CMAP wasslightly greater for AIDP patients than for AMAN pa-tients and normal subjects, but the differences were notstatistically significant (see Fig 1).

Recovery Cycle and Threshold ElectrotonusThe pattern of the recovery cycle was similar for nor-mal controls and patients with AMAN or AIDP, withrelative refractoriness less than 4 milliseconds, super-normality maximal at approximately the 7-millisecondconditioning-test interval, and late subnormality maxi-mal at approximately 40 milliseconds (Fig 2). How-ever, refractoriness, defined as the extent of the thresh-old increases during the relatively refractory period (eg,conditioning-test intervals of 2 and 2.5 milliseconds),was significantly greater in AMAN patients than innormal subjects (see Fig 2A; p � 0.0001). In 7 of the10 AMAN patients, refractoriness at the 2-millisecondinterval was higher than three standard deviationsabove the mean value for normal subjects (Fig 3A).When compared with patients with AIDP, chronic in-flammatory demyelinating polyneuropathy, diabetes

182 Annals of Neurology Vol 52 No 2 August 2002

mellitus, or amyotrophic lateral sclerosis, patients withAMAN had significantly greater refractoriness at the2-millisecond interval (Fig 4; p � 0.01). At the samestimulus sites (median nerve at wrist), refractoriness ofsensory axons was similar for AMAN patients and nor-mal subjects (see Fig 2C). The recovery cycles were al-most identical for normal subjects and AIDP patients(see Figs 2B and 3).

In threshold electrotonus, the threshold changes pro-duced by subthreshold depolarizing and hyperpolariz-ing currents were similar for AMAN patients and nor-mal subjects. AIDP patients tended to have the smallerslow phase of depolarizing threshold change to depo-larizing current than normal subjects, but the differ-ence was not statistically significant (p � 0.09).

Fig 1. Stimulus-response curves using stimuli of 1.0-millisecond duration, and strength-duration time constant forthe 50% compound muscle action potential (CMAP) in nor-mal subjects (n � 37), and in patients with acute motor ax-onal neuropathy (AMAN; n � 10) or acute inflammatorydemyelinating polyneuropathy (AIDP; n � 8). Error bars in-dicate standard error.

Fig 2. Recovery cycle of axonal excitability in normal subjectsand (A) patients with acute motor axonal neuropathy(AMAN; n � 10) or (B) acute inflammatory demyelinatingpolyneuropathy (AIDP; n � 8). Data for each patient groupare compared with those for age-matched normal subjects(“normal-young,” 20–44 years; n � 20; “normal-old,”45–80 years; n � 17). (C) The increase in “refractoriness” ofmotor axons in AMAN (A) did not involve sensory axons.Data are given as mean � standard error.


Serial Studies of Refractoriness and CompoundMuscle Action PotentialsFigure 5 shows serial changes in refractoriness at the2-millisecond interval and the amplitude of distalCMAPs of the median nerve in seven AMAN patients

who underwent serial studies. Refractoriness decreasedor returned to the normal range within 30 days of theonset of neurological symptoms in most of the pa-tients. There was an inverse relationship between thechange in CMAP amplitude and the change in refrac-toriness when the data were normalized to allow com-parison across subjects (p � 0.025).

The Effects of Local Cooling of the Muscle onRecovery Cycle in a Normal SubjectTo study changes in the recovery cycle due to changesin distal refractoriness only, we applied local cooling tothe motor point of the abductor pollicis brevis musclewith an ice pack in a normal subject. Figure 3C showsthe recovery cycle curves before and after cooling.Temperature over the muscle was 33.6°C before and29.0°C after cooling, whereas temperature at the wristwas maintained at 33.9°C. Refractoriness at the 2.0-and 2.5-millisecond intervals increased abruptly duringcooling, mimicking the pattern observed in AMAN pa-tients. Stimulus-response curves, strength-durationtime constant and threshold electrotonus did notchange significantly with distal cooling, presumably be-cause they reflect properties of the axonal membrane atthe stimulation site.

DiscussionOur results show several differences in axonal excitabil-ity properties for motor axons of patients with AMANand those with AIDP in vivo. The main findings were

Fig 3. Superimposed recovery cycle curves of patients with (A)acute motor axonal neuropathy (AMAN; n � 10) or (B)acute inflammatory demyelinating polyneuropathy (AIDP; n �8). Dotted lines indicate 95% confidence intervals for age-matched normal subjects. (C) Data for a single normal sub-jects in whom recordings were made before (33.6°C) and after(29.0°C) local cooling applied to the motor point of the ab-ductor pollicis brevis.

Fig 4. Refractoriness at the conditioning-test interval of 2 mil-liseconds in normal subjects, and patients with acute motoraxonal neuropathy (AMAN), acute inflammatory demyelinat-ing polyneuropathy (AIDP), chronic inflammatory demyelinat-ing polyneuropathy (CIDP), diabetic neuropathy (DM), andamyotrophic lateral sclerosis (ALS). Error bars indicate stan-dard errors. (asterisk) p � 0.05, compared with the othergroups.


markedly greater refractoriness for AMAN patients andits rapid normalization, associated with a recovery inamplitude of CMAPs. Excitability indices did not showsignificant changes in the median nerve at the wrist ofAIDP patients. These findings suggest that pathology ismore prominent in the distal nerve segments than atthe wrist in both AMAN and AIDP, and that mecha-nisms of conduction failure are different in the twosubtypes of GBS.

The changes in excitability properties in AMAN

were characterized by increased refractoriness. Greaterrefractoriness was not seen in patients with amyotro-phic lateral sclerosis or diabetic neuropathy (see Fig4), suggesting that it was not the result merely of ax-onal degeneration. Threshold tracking provides reli-able data about the excitability properties at the pointof stimulation, but does so only when impulse trans-mission between the stimulus site and the muscle issecure. An increase in refractoriness in our recordingstherefore may reflect either a true increase in refrac-toriness at the wrist or an impaired refractory periodof transmission distal to the wrist, producing trans-mission failure of the second of a pair of closelyspaced impulses.32 The abnormal recovery cycles re-corded from individual AMAN patients (see Fig 3A)were characterized by abrupt departures from the nor-mal range at the short interstimulus interval. Thecurves differ in appearance from those previously re-corded in conditions where refractoriness at the wristwas deliberately prolonged by ischemia, by depolar-ization by applied currents,25 or by cooling,26 in allof which the recovery cycles had smooth curves. Wetherefore interpret the increased refractoriness inAMAN patients as being caused by an impaired re-fractory period of transmission distal to the wrist,probably in the distal nerve terminals. This interpre-tation was supported by the findings shown in Figure3C, in which a similar abrupt deviation from a nor-mal recovery cycle was produced by local cooling atthe motor point.

Our recovery cycle data therefore provide evidencefor a critically reduced safety factor for impulse con-duction in the distal nerve terminals of AMAN pa-tients.8,10 Because the site of conduction failure wasremote from the stimulus site, our data provide nodirect evidence on the biophysical basis for the re-duced safety factor, but some speculations are in or-der. One hypothesis, as described in the introduction,is a reduction in the number of functioning Na�

channels. Blockade of Na� channels can cause eitherconduction slowing or conduction block and wouldaccount for their rapid reversal.8 This is seen in hu-man poisoning by tetrodotoxin and saxitoxin, whichspecifically block voltage-dependent Na� channels:the conduction slowing and decreased CMAP ampli-tudes return to normal within days.33,34 Na� channelfunction is altered by tissue temperature,26 and thesimilar patterns of change in refractoriness after localcooling at the motor point support the possibility ofaltered Na� channel function in AMAN. In normalsubjects, voluntary contraction impairs the refractoryperiod of transmission of impulses 2 to 3 millisecondsapart, probably in the distal nerve terminals of themotor axons.35 This normal physiological limitationcould become clinically relevant if pathology de-

Fig 5. Refractoriness (conditioning-test interval, 2 milliseconds)and amplitude of compound muscle action potentials (CMAP)after median nerve stimulation at the wrist in seven patientswith acute motor axonal neuropathy (AMAN), who under-went sequential studies. Open symbols on the right indicatemean (�SE) of data for normal subjects for refractoriness(n � 37) and CMAP amplitude (n � 101). There was aninverse relationship between the change in CMAP amplitudeand the change in refractoriness (p � 0.025).


creased the safety margin for impulse conductionfurther.

An alternative explanation for the reduced safetyfactor in AMAN is suggested by autopsy studies,36

which have shown that the first visible signs of im-mune attack are the presence of macrophages overlay-ing the nodal gap, followed by insinuation of macro-phage processes under the myelin terminal loops intothe periaxonal spaces. The first step could reduce thesafety factor by increasing the resistance of nodal cur-rents, and the second by short-circuiting them. Dis-ruption of the axo–glial junction by macrophage pro-cesses would produce a type of demyelination(“myelin detachment”)37 that can block conductionwith only mild slowing, because the primary electricalconsequence is a decrease in the effective nodal leakresistance. This mechanism could account for the in-creased refractoriness and its rapid reversal seen in ourAMAN patients, whereas the subsequent invasion ofthe periaxonal space by macrophages could lead toirreversible degeneration.2,36

Whatever its mechanism, the reduced safety factor inthe distal nerve in AMAN can account for both con-duction block in some fibers and the prolonged refrac-tory period of transmission in others. Similarly, therapid recovery of the safety factor accounts for the par-allel recovery of CMAP amplitude and reduction in re-fractoriness documented in Figure 5.

Unexpectedly, the AIDP patients showed no signif-icant changes in excitability of median nerve axons atthe wrist, despite profound prolongation of distal la-tencies. Exposure of paradodal or internodal axolemmaby demyelination should affect �SD, supernormalityand threshold electrotonus.23 For example, paranodalfast K� channels limit the size of supernormality: whenfast K� channels are exposed by demyelination, super-normality decreases significantly.23 The negative resultsin this study suggest that demyelination is more severedistally in the nerve terminals largely sparing the wristsegment.

In conclusion, the differences in membrane proper-ties suggest that the predominantly distal targets of theimmune attack are different for AMAN and AIDP,2,38

and that the mechanism of conduction failure is differ-ent. Our data indicate that in the acute phase ofAMAN the safety factor for impulse transmission iscritically reduced in distal nerve segments. Because ofinaccessibility of the nerve terminals to excitability test-ing, further studies are required to determine themechanisms of conduction block in AMAN.

This study was supported in part by a grant for Neuroimmunologi-cal Diseases (GBS1-4, T.H. and S.K.) from the Ministry of Healthand Welfare of Japan.

References1. Feasby TE, Gilbert JJ, Brown WF, et al. An acute axonal form

of Guillain-Barre polyneuropathy. Brain 1986;109:1115–1126.2. Griffin JW, Li CY, Ho TW, et al. Guillain-Barre syndrome in

northern China. The spectrum of neuropathological changes inclinically defined cases. Brain 1995;118:575–595.

3. Ho TW, Mishu B, Li CY, et al. Guillain-Barre syndrome innorthern China. Relationship to Campylobacter jejuni infectionand anti-glycolipid antibodies. Brain 1995;118:597–605.

4. Choudhury D, Arora A. Axonal Guillain-Barre syndrome: acritical review. Acta Neurol Scand 2001;103:267–277.

5. Asbury AK, Anarson BG, Adams RD. The inflammatory lesionin idiopathic polyneuritis. Its role in pathogenesis. Medicine1969;48:173–215.

6. Prineas JW. Pathology of the Guillain-Barre syndrome. AnnNeurol 1981;9:6–19.

7. Haden RDM, Cornblath DR, Hughes RAC, et al. Electrophys-iological classification of Guillain-Barre syndrome: clinical asso-ciations and outcome. Ann Neurol 1998;44:780–788.

8. Kuwabara S, Yuki N, Koga M, et al. IgG anti-GM1 antibody isassociated with reversible conduction failure and axonal degen-eration in Guillain-Barre syndrome. Ann Neurol 1998;44:202–208.

9. Ogawara K, Kuwabara S, Mori M, et al. Axonal Guillain-Barresyndrome: relation to anti-ganglioside antibodies and Campy-lobacter jejuni infection in Japan. Ann Neurol 2000;48:624–631.

10. Ho TW, Lin CY, Cornblath DR, et al. Patterns of recovery inthe Guillain-Barre syndromes. Neurology 1997;48:695–700.

11. Kuwabara S, Asahina M, Koga M, et al. Two patterns of clin-ical recovery in Guillain-Barre syndrome with IgG anti-GM1antibody. Neurology 1998;51:1656–1660.

12. Kuwabara S, Mori M, Ogawara K, et al. Axonal involvementat the common entrapment sites in Guillain-Barre syndromewith IgG anti-GM1 antibody. Muscle Nerve 1999;22:840 – 845.

13. Waxman SG. Sodium channel blockade by antibodies: a newmechanism of neurological disease. Ann Neurol 1995;37:421–423.

14. Enders U, Karch H, Toyka KV, et al. The spectrum of immuneresponses to Campylobacter jejuni and glycoconjugates inGuillain-Barre syndrome or in other neuroimmunological dis-orders. Ann Neurol 1993;34:136–144.

15. Rees JH, Gregson NA, Hughes RAC. Anti-GM1 antibodies inGuillain-Barre syndrome and their relationship to Campy-lobacter jejuni infection. Ann Neurol 1995;38:809–816.

16. Vriesendorp FJ, Mishu B, Blaser MJ, Koski CL. Serum anti-bodies to GM1, GD1b, peripheral nerve myelin, and Campy-lobacter jejuni in patients with Guillain-Barre syndrome andcontrols: correlation and prognosis. Ann Neurol 1993;34:130–135.

17. Santro M, Uncini A, Corpo M, et al. Experimental conductionblock induced by serum from a patient with anti-GM1 anti-bodies. Ann Neurol 1992;31:385–390.

18. Harvey GK, Toyka KV, Zielasek J, et al. Failure of anti-GM1IgG or IgM to induce conduction block following intraneuraltransfer. Muscle Nerve 1995;18:338–394.

19. Arasaki K, Kusunoki S, Kudo N, Kanazawa I. Acute conduc-tion block in vitro following exposure to antiganglioside sera.Muscle Nerve 1993;16:587–593.

20. Takigawa T, Yasuda H, Kikkawa R, et al. Antibodies againstGM1 ganglioside affect K� and Na� currents in isolated ratmyelinated nerve fibers. Ann Neurol 1995;37:436–442.


21. Weber F, Rudel R, Aulkemeyer O, Brinkmeier H. Anti-GM1antibodies can block neuronal voltage-gated sodium channels.Muscle Nerve 2000;23:1414–1420.

22. Hirota N, Kaji R, Bostock H, et al. The physiological effect ofanti-GM1 antibodies on saltatory conduction and transmem-brane currents in single motor axons. Brain 1997;120:2159–2169.

23. Bostock H, Cikurel K, Burke D. Threshold tracking techniquesin the study of human peripheral nerve. Muscle Nerve 1998;21:137–158.

24. Kiernan M, Burke D, Andersen K, Bostock H. Multiple mea-sures of axonal excitability: a new approach in clinical testing.Muscle Nerve 2000;23:399–409.

25. Kiernan M, Bostock H. Effects of membrane polarization andischaemia on the excitability properties of human motor axons.Brain 2000;123:2542–2551.

26. Kiernan MC, Cikurel K, Bostock H. Effects of temperature onthe excitability properties of human motor axons. Brain 2001;124:816–825.

27. Kuwabara S, Cappelen-Smith C, Lin C, et al. Excitability prop-erties of median and peroneal motor axons. Muscle Nerve2000;23:1365–1373.

28. Asbury AK, Cornblath DR. Assessment of current diagnosticcriteria for Guillain-Barre syndrome. Ann Neurol 1990;27(suppl):S21–S24.

29. Weiss G. Sur la possibilite de rendre comparables entre eux lesappareils servant l’excitation electrique. Arch Ital Biol 1902;35:413–446.

30. Yuki N, Taki T, Handa S. Antibodies to GalNAc-GD1a andGalNAc-GD1b in Guillain-Barre syndrome subsequent toCampylobacter jejuni enteritis. J Neuroimmunol 1996;71:155–161.

31. Yuki N, Ang CW, Koga M, et al. Clinical features and responseto treatment in Guillain-Barre syndrome associated with anti-bodies to GM1b ganglioside. Ann Neurol 2000;47:314–321.

32. McDonald WI, Sears TA. The effects of experimental demyeli-nation on conduction in the central nervous system. Brain1970;93:583–598.

33. Oda K, Araki K, Totoki T, Shibasaki H. Nerve conductionstudy of human tetrodotoxication. Neurology 1989;39:743–745.

34. Long RR, Sargent JC, Hammer K. Paralytic shellfish poisoning:a case report and serial electrophysiologic observations. Neurol-ogy 1990;40:1310–1312.

35. Kuwabara S, Lin C S, Mogyoros I, et al. Voluntary contractionimpairs the refractory period of transmission in healthy humanaxons. J Physiol (Lond) 2001;531:265–275.

36. Griffin JW, Li CY, Macko C, et al. Early nodal changes in theacute motor axonal neuropathy pattern of Guillain-Barre syn-drome. J Neurocytol 1996;25:33–51.

37. Bostock H. The pathophysiology of demyelination. In: Hern-don RM, Seil FJ, eds. Multiple sclerosis. Current status of re-search and treatment. New York: Demos Publications, 1994:89–112.

38. Hafer-Macko C, Hsieh S-T, Li CY, et al. Acute motor axonalneuropathy: an antibody-mediated attack on axolemma. AnnNeurol 1996;40:635–644.


differences in membrane properties of axonal and demyelinating guillain-barré syndromes

Documents