ABSTRACT: Chronic inflammatory demyelinating polyneuropathy (CIDP)
is characterized by multifocal demyelination along the course of the nerves,
and involvement of the intermediate segments may correlate with more
severe demyelination associated with breakdown of the blood–nerve barrier.
Threshold electrotonus was used to study whether altered membrane prop-
erties of the median nerve at the wrist (intermediate segment) are associ-
ated with clinical profiles in 21 CIDP patients. In response to hyperpolarizing
conditioning stimuli, the threshold changes were significantly greater for
CIDP patients than for normal controls (n
49). The pattern was similar to
that of 11 patients with Charcot-Marie-Tooth disease type 1a, who exhibited
abnormally high thresholds to hyperpolarizing currents. The abnormal
threshold electrotonus was present in 48% of the CIDP patients and was
associated with longer disease duration, more severe disability, poorer
response to immune treatments, and slower nerve conduction velocities.
Threshold electrotonus can be used to detect demyelination at the tested
sites and may provide new information about pathophysiology and distribu-
tion patterns of demyelination in CIDP.
Muscle Nerve 29: 28–37, 2004
THRESHOLD ELECTROTONUS IN CHRONIC
INFLAMMATORY DEMYELINATING
POLYNEUROPATHY: CORRELATION
WITH CLINICAL PROFILES
JIA-YING SUNG, MD,1 SATOSHI KUWABARA, MD,1 RYUJI KAJI, MD, PhD,2
KAZUE OGAWARA, MD,1 MASAHIRO MORI, MD,1 KAZUAKI KANAI, MD,1
HIROYUKI NODERA, MD,2 TAKAMICHI HATTORI, MD,1 and HUGH BOSTOCK, PhD3
1 Department of Neurology, Chiba University School of Medicine,
1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
2 Department of Clinical Neuroscience, Hospital of the University
of Tokushima, Tokushima, Japan
3 Sobell Department of Neurophysiology, Institute of Neurology,
London, United Kingdom
Accepted 20 August 2003
Chronic inflammatory demyelinating polyneurop-
athy (CIDP) is a demyelinating disease of the periph-
eral nerves in which myelin is the presumed target of
the immune attack.12 It is likely that CIDP is a het-
erogeneous disorder, having a wide range of clinical
presentation ranging from symmetric polyneurop-
athy to mononeuropathy multiplex20,24,25 and from a
monophasic to a relapsing course.2,10,21 Chronic in-
flammatory demyelinating polyneuropathy is charac-
terized by multifocal demyelination that can involve
the distal nerve terminals, intermediate nerve seg-
ments, and nerve roots.12,18 Distribution of demyeli-
native lesions varies among CIDP patients; patholog-
ical studies have shown demyelination predominant
in the nerve roots,12 whereas electrophysiological
studies have demonstrated conduction block or slow-
ing predominant in the distal nerve terminals11 or
localized in the intermediate nerve segments.18,24
Previous reports have suggested that CIDP consists
of subtypes with varying predilections for lesions
along the course of the nerve and that the diffusely
distributed demyelination correlates with severe dis-
ability, refractoriness to treatment, and active demy-
elination associated with breakdown of the blood–
nerve barrier.18,22,23
Abbreviations:
SD, strength–duration time constant; AIDP, acute inflam-
matory demyelinating polyneuropathy; CIDP, chronic inflammatory demyeli-
nating polyneuropathy; CMAP, compound muscle action potential; CMT,
Charcot-Marie-Tooth; TE, threshold electrotonus; TEd, threshold reduction
under conditioning depolarizing current in the threshold electrotonus record-
ings; TEh, threshold reduction under conditioning hyperpolarizing current in
the threshold electrotonus recordings
Key words: chronic inflammatory demyelinating polyneuropathy; demyelina-
tion; myelin property; potassium channel; threshold electrotonus
Correspondence to: S. Kuwabara; e-mail: kuwabara@med.m.chiba-u.ac.jp
© 2003 Wiley Periodicals, Inc.
28 Threshold Electrotonus in CIDP MUSCLE & NERVE January 2004

Demyelination affects passive and active axonal
membrane properties: segmental demyelination can
change nodal and myelin properties and expose the
paranodal and internodal axonal membrane, alter-
ing Na and K currents.4,8,26 A number of axonal
excitability indices (such as strength–duration prop-
erties, threshold electrotonus, refractoriness, and su-
pernormality) can be measured as part of the rou-
tine clinical assessment using the threshold tracking
technique.8,15,19 Among the excitability indices,
threshold electrotonus is likely to reflect myelin
properties, because this technique uses long sub-
threshold conditioning currents to charge the inter-
nodes of tested axons. A previous study investigating
these indices in 11 CIDP patients showed shorter
strength–duration time constant, less refractoriness,
and supernormality in CIDP patients than in normal
subjects.8 There was no significant change in thresh-
old electrotonus, although threshold electrotonus
curves were variable among patients, and some
showed greater threshold changes to, particularly,
hyperpolarizing currents. Because excitability testing
measures the membrane properties at the point of
stimulation, and demyelinative lesions distribute
multifocally along the course of the nerve in CIDP,
the distribution pattern of demyelination should
largely determine the findings of the excitability test-
ing, including threshold electrotonus.
To investigate whether the changes in threshold
electrotonus correlate with clinical profiles, we ap-
plied this technique to the median nerve at the wrist
(intermediate nerve segment) of patients with CIDP
and compared results with the corresponding clini-
cal features, responses to treatment, and findings of
conventional nerve conduction studies. Because
changes in threshold electrotonus have rarely been
examined in human demyelinating neuropathies,8,19
patients with Charcot-Marie-Tooth disease (CMT)
type 1a (CMT1a), in whom the median nerve at the
wrist should be affected, were also examined to in-
vestigate how demyelination affects threshold elect-
rotonus.
METHODS
Subjects. Twenty-one CIDP patients (14 men and 7
women), seen at Chiba University Hospital between
2000 and 2002, were studied. Their mean age was 45
years (range, 19–78 years), and their condition ful-
filled the research criteria for the diagnosis of CIDP
proposed by the American Academy of Neurology.1
We excluded patients with multifocal motor neurop-
athy or monoclonal gammopathy, because their clin-
ical, electrophysiological, and immunological pro-
files are somewhat different from those of idiopathic
CIDP.9 At the time of examination, 13 patients were
in the initial progressive or relapsing phase, and the
remaining eight were in partial remission. Clinical
disabilities were evaluated on the Hughes functional
grading scale (grade 1, minor symptom and signs,
able to run; grade 2, able to walk 5 m without aids;
grade 3, able to walk 5 m with aids; grade 4, chair- or
bed-bound). Treatment was considered effective
when the patient’s condition improved by 1 or more
on the Hughes scale.
Fifteen patients with the acute inflammatory
demyelinating polyneuropathy (AIDP) type of
Guillain–Barre´ syndrome and 11 patients with ge-
netically confirmed CMT1a were also examined. A
part of the data for AIDP patients has been de-
scribed elsewhere.19 Patients with CMT1a were ex-
amined at Chiba University Hospital (n
5) or
Tokushima University Hospital (n
6). The con-
trol data of multiple excitability measurements
using threshold tracking were obtained from 49
age-matched healthy subjects with mean age of 43
years (range, 18–78 years).
All subjects gave their informed consent, and the
study had the approval of the ethics committee of
the Chiba University School of Medicine.
Threshold Electrotonus Recording. Threshold track-
ing was used to measure the excitability of the me-
dian nerve at the wrist. The principle of threshold
electrotonus is described elsewhere.3,5 The current
required to produce a compound muscle action po-
tential (CMAP) that is 40% of maximum was deter-
mined with a computer program (qtrac version 4.3
with multiple excitability protocol trondhm, written
by H. Bostock, Institute of Neurology, London) as
described elsewhere.15,16 The current required to
specify 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 stimulation, the active electrode was
placed over the nerve at the wrist, and the remote
electrode was placed 10 cm proximal over forearm
muscle. Skin temperature near the stimulus site was
maintained above 32.0°C.
Membrane potential was altered using subthresh-
old polarizing currents that were 40% of the uncon-
ditioned threshold. Depolarizing and hyperpolariz-
ing currents were used, each lasting 100 ms, and
their effects on the threshold for the test CMAP were
measured. The three following stimulus combina-
tions were tested in turn: test stimulus alone (to
measure the control threshold current), test stimu-
lus plus depolarizing conditioning current, and test
Threshold Electrotonus in CIDP MUSCLE & NERVE January 2004 29