DifferencesinMembraneProperties
ofAxonalandDemyelinating
Guillain-Barre´Syndromes
SatoshiKuwabara,MD,
1
KazueOgawara,MD,
1
Jia-YingSung,MD,
1
MasahiroMori,MD,
1
KazuakiKanai,MD,
1
TakamichiHattori,MD,
1
NobuhiroYuki,MD,
2
CindyS.-Y.Lin,BE,MEngSc,
3
DavidBurke,MD,DSc,
3
andHughBostock,PhD,FRS
4
Guillain-Barre´syndromeisclassifiedintoacutemotoraxonalneuropathy(AMAN)andacuteinflammatorydemyelinat-
ingpolyneuropathy(AIDP)byelectrodiagnosticandpathologicalcriteria.InAMAN,theimmuneattackappearsdirected
againsttheaxolemmaandnodesofRanvier.Thresholdtrackingwasusedtomeasureindicesofaxonalexcitability
(refractoriness,supernormality,andthresholdelectrotonus)formediannerveaxonsatthewristofpatientswithAMAN
(n
10)andAIDP(n
8).Refractoriness(theincreaseinthresholdcurrentduringtherelativerefractoryperiod)was
greatlyincreasedinAMANpatients,buttheabruptnessofthethresholdincreasesatshortinterstimulusintervalsindi-
catedconductionfailuredistaltothestimulation(ie,anincreasedrefractoryperiodoftransmission).Duringthe4week
periodfromonset,thehighrefractorinessreturnedtowardnormal,andtheamplitudeofthecompoundmuscleaction
potentialincreased,consistentwithimprovementinthesafetymarginforimpulsetransmissioninthedistalnerve.In
contrast,refractorinesswasnormalinAIDP,eventhoughtherewasmarkedprolongationofdistallatencies.Supernor-
malityandthresholdelectrotonuswerenormalinbothgroupsofpatients,suggestingthat,atthewrist,membrane
potentialwasnormalandpathologywasrelativelyminor.Theseresultssupporttheviewthatthepredominantlydistal
targetsofimmuneattackaredifferentforAMANandAIDP.PossiblemechanismsforthereducedsafetyfactorinAMAN
arediscussed.
AnnNeurol2002;52:180–187
Guillain-Barre´syndrome(GBS)isclassifiedintodemy-
elinatingandaxonalcategoriesbyclinical,electrophysi-
ological,andpathologicalcriteria.
1–4
InNorthAmerica
andEurope,theusualformofGBSisacuteinflamma-
torydemyelinatingpolyneuropathy(AIDP).
5–7
Incon-
trast,aconsiderablenumberofGBSpatientshaveacute
motoraxonalneuropathy(AMAN)inChina
3
andJa-
pan.
8,9
AutopsystudiesofAMANpatientshavefound
extensiveaxonaldegenerationofmotorfibers,
2
butmost
AMANpatientsrecoverwell
10
orevenfasterthanpa-
tientswithAIDP.
11
Alikelyinterpretationforthequick
recoveryisimmune-mediatedreversibleeffectsonthe
axolemma.
8,10
InAMAN,previouselectrodiagnostic
studieshaveshownthatbothquickresolutionofcon-
ductionblockinthedistalnerveterminals
8
andatthe
commonentrapmentsites
12
andthetimecourseofthis
recoveryaredifferentfromthoseinAIDPpatients.
ThemechanismsforconductionblockinAMANare
unknown,butblockageofNa


channelshasbeenpos-
tulatedasapossiblepathophysiologyinsuchdisor-
ders.
10–13
Hightitersofserumanti–GM1antibodiesarefound
in10to42%ofpatientswithGBS,
3,9,14–16
but
whetherthisantibodyplaysaroleinthepathophysiol-
ogyofaxonaldysfunctionisamatterofcontroversy.
Passivetransferofanti–GM1antibodiestoanimal
nerveshasbeenshowntocausenerveconductionblock
insomestudies,
17
butnotinothers.
18
Similarly,incu-
bationofisolatednervepreparationsinvitrowithanti–
GM1antibodieshasdecreasedNa


currentsorpro-
ducedconductionblockinsomestudies,
19–21
butnot
inothers.
22
Fromthe
1
DepartmentofNeurology,ChibaUniversitySchoolof
Medicine,Chiba;
2
DepartmentofNeurology,DokkyoUniversity
SchoolofMedicine,Tochigi,Japan;
3
PrinceofWalesMedicalRe-
searchInstitute,UniversityofNewSouthWalesandCollegeof
HealthSciences,UniversityofSydney,Australia;and
4
SobellDe-
partmentofNeurophysiology,InstituteofNeurology,Queen
Square,London,UnitedKingdom.
ReceivedMar1,2002,andinrevisedformApr5.Acceptedfor
publicationApr6.
Published?online?Jun?21,?2002,?in?Wiley?InterScience
(www.interscience.wiley.com).DOI:10.1002/ana.10275
AddresscorrespondencetoDrKuwabara,DepartmentofNeurol-
ogy,ChibaUniversitySchoolofMedicine,1-8-1Inohana,Chuo-
ku,Chiba260-8670,Japan.E-mail:kuwabara@med.m.chiba-u.ac.jp
180?? 2002Wiley-Liss,Inc.

In the 1990s, the threshold tracking technique was
developed to measure several indices of axonal excitabil-
ity (such as refractoriness, supernormality, late subnor-
mality, threshold electrotonus, and strength-duration
properties), noninvasively in human subjects.
23–27
These
indices 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 it
might clarify the mechanism of conduction failure in
AMAN, and the differences between AMAN and AIDP.
Subjects and Methods
Subjects
Eighteen consecutive GBS patients (15 men and 3 women)
were studied (Table). Their condition fulfilled the clinical
criteria 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 patients
were treated with intravenous immunoglobulin infusions
(n  11) or plasmapheresis (n  2), and pretreatment serum
samples taken during the first 10 days after onset were
stored.
For threshold-tracking studies, control data were obtained
from 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 the
study had the approval of the ethical committee of Chiba
University School of Medicine.
Conventional Electrodiagnostic Studies
Nerve conduction studies were performed using conventional
procedures. Motor studies were made on the median, ulnar,
tibial, and peroneal nerves. Sensory nerve conduction studies
were performed to antidromic stimulation of the median
nerve. Patients were classified as having AIDP or AMAN on
the basis of the electrodiagnostic criteria of Ho and col-
leagues.
3
Multiple Excitability Measures Using
Threshold Tracking
In the threshold-tracking studies, the current required to
produce a compound muscle action potential (CMAP) that
was 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 a
specified CMAP size (40% of maximum) is referred to as the
“threshold” for that CMAP size. The CMAP was recorded
from the abductor pollicis brevis. For median nerve stimula-
tion, the active electrode was placed over the nerve at the
wrist, and the remote electrode was placed 10cm proximal
over forearm muscle. Skin temperature near the stimulus site
was maintained above 32.0°C.
The stimulus-response curves were measured using test
stimuli of duration 0.2 and 1.0 milliseconds. From these
curves, strength-duration time constant (
SD
) was calculated
using the following formula
27,29
:


SD
 0.2I
0.2
 I
1.0
/I
1.0
 0.2I
0.2

where I
0.2
and I
1.0
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)/Gender
Cranial Nerve
Palsy
Sensory
Loss
Hughes
Grade
a
Antiganglioside IgG
Antibody Against
Acute motor axonal neuropathy
1 22/M No No 3 GM1b, GalNAc-GD1a
2 17/M No No 4 GM1b, GalNAc-GD1a
3 48/M No No 2 GM1, GalNAc-GD1a
4 35/M No No 3 GalNAc-GD1a
5 27/M No No 2 GM1b, GalNAc-GD1a
6 32/F No No 2 GM1b
7 17/M Facial No 5 GM1, GM1b, GalNAc-GD1a
8 26/M No No 4 GM1, GM1b
9 34/M No No 2
10 24/M No No 2 GM1, GM1b
Acute inflammatory demyelinating polyneuropathy
1 72/F Facial, bulbar Yes 4
2 70/M Facial Yes 4
3 56/F No Yes 3
4 57/M No Yes 3
5 71/M Facial Yes 2
6 59/M Facial, bulbar Yes 4
7 56/M No Yes 2
8 36/M Facial Yes 3
a
At 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