Clinical & Experimental

Neuroimmunology
Clinical and Experimental Neuroimmunology 7 (2016) 312–319

REVIEW ARTICLE

syndrome
Pathology of Guillain–Barre
Yuta Nakano and Takashi Kanda
Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan

Keywords
acute inflammatory demyelinating polyradicu-
loneuropathy; acute motor and sensory axonal
neuropathy; acute motor axonal neuropathy;
Guillain–Barr

e syndrome; pathology
Correspondence
Takashi Kanda, MD, PhD, Department of Neu-
rology and Clinical Neuroscience, Yamaguchi
University Graduate School of Medicine, 1-1-1
Minamikogushi, Ube, Yamaguchi 755-8505,
Japan.
Tel: +81-836-22-2714
Fax: +81-836-22-2364
Email: tkanda@yamaguchi-u.ac.jp
Received: 15 September 2016; revised:
26 September 2016; accepted: 26 September
2016.
Abstract
Guillain–Barr
e syndrome (GBS), a disease affecting the peripheral nervous
system, is now well known. However, the disease concept has evolved over
successive periods. For example, for approximately nine decades from the
first report of GBS, it was considered to have a spinal cord origin. After the
first clinical report, the accumulation of detailed clinicopathological data
showed that GBS is composed of two distinct clinicopathological entities:
acute inflammatory demyelinating polyneuropathy, and acute motor axonal
neuropathy or acute motor and sensory axonal neuropathy. Acute inflam-
matory demyelinating polyneuropathy is characterized by the patchy distri-
bution of demyelinative foci throughout the peripheral nervous system,
whereas acute motor axonal neuropathy/acute motor and sensory axonal
neuropathy shows primary axonal degeneration in the peripheral nervous
system, which is particularly accentuated at the spinal nerve roots. The pur-
pose of the present article was to provide an overview of the previous pub-
lications regarding the pathology of GBS and to thereby elucidate the
pathological mechanisms of this still threatening disorder from a pathologi-
cal viewpoint. The critical pathological feature of acute inflammatory
demyelinating polyneuropathy is the complement–macrophage-induced
cytotoxic damage on the plasmalemma of the Schwann cells, whereas that
of acute motor axonal neuropathy/acute motor and sensory axonal neu-
ropathy is the antibody–complement-mediated immune attack on the axo-
lemma at the nodes of Ranvier.

demyelination. Electron microscopic techniques3–6

Introduction
Guillain–Barr
e syndrome (GBS) is now a well-
known disorder of the peripheral nervous system
(PNS). Nevertheless, for approximately nine decades
from the first report of GBS, the disease was consid-
ered to have a spinal cord origin.1
Since the first clinical report, the accumulation of
detailed clinicopathological data has shown that the
classical form of GBS was primary inflammatory
demyelinative peripheral neuropathy. Consequently,
GBS was recognized as “acute inflammatory
demyelinating polyneuropathy (AIDP).”
In 1986, the concept of the axonal type of GBS
was proposed.2 It evoked controversy at the time,
chiefly because the axonal damage of the myelinated
fibers might have occurred as a result of Wallerian
degeneration because of intense inflammatory
and immunohistochemical approaches6,7 supported
the presence of primary axonal degeneration. Now
the disease concept of the axonal form of GBS has
been established: namely, acute motor or motor and
sensory axonal neuropathy (AMAN and AMSAN).
The aim of the present article was to provide an
overview of the previous publications on the pathol-
ogy of GBS and to thereby elucidate the pathological
mechanisms underlying this still threatening disor-
der.
Pathology of AIDP
Where are the lesions of AIDP located?
GBS became widely known to the world through a
clinical report that was published in 1916, in which
three French neurologists Georges Guillain, Jean-

312 © 2016 Japanese Society for Neuroimmunology

Y. Nakano and T. Kanda Overview of the previous publications

Alexandre Barr
e and Andr
e Strohl described two

cases of acute polyneuropathy.8 More than 50 years
had passed since the first case of GBS was reported
in 1859 by Landry (Landry ascending paralysis);
however, the precise pathological aspects of this dis-
ease were obscure at that time.1
This delay was likely due – in part – to the stan-
dard autopsy sampling sites: the distal peripheral
nerves were rarely examined at that time. Thus,
central chromatolysis, which is now considered a
secondary pathological finding of the anterior horn
cells (because of the severe damage of the peripheral
nervous axon cylinders), was only occasionally
detected. This led to the incorrect assumption that
the origin of GBS was the spinal cord, rather than
the peripheral nerves.9–12
Haymaker and Kernohan examined 50 autopsied
fatal GBS cases with clinical courses of between 2
and 46 days in 1949, and concluded that the site
most vulnerable to GBS was the spinal roots.13 All of
Figure 1 The VI cranial nerve presenting patchily distributed demyeli-
their cases involved USA military personnel during nated foci (arrows). Scale bar, 1 cm. Reproduced from Nakano et al.30
World War II. Through their detailed pathological with permission.
observations, they summarized the histological
sequence of the progressive disease process as fol-
lows: “edema during the first 3 or 4 days, with swel- lesion distribution, sural nerve biopsy specimens
ling and irregularity of the myelin sheaths and axis from GBS patients do not usually capture the precise
cylinders beginning on the 5th day, the appearance demyelinative foci; thus, only normal pathology or
of a few lymphocytes on the 9th day and phagocytes secondary Wallerian degeneration was observed.
on the 11th day, and Schwann cell proliferation on
the 13th day.’’ They seemed to regard the early ede-
How does demyelination occur in AIDP?
matous change as the main causative pathological
finding in GBS and the infiltration of lymphocytes as The next issue is the pathological elucidation of the
the reparative reaction, which tended to emerge in a demyelinative process in AIDP. Electron micro-
relatively late stage of the disease process. These scopic techniques were very useful for this purpose
pathological changes were most prominent at the (Figs 2–4).
motor and sensory spinal roots – these sites were In 1969, Wi
sniewski et al.15 documented a post-
thought to suffer the most damage from GBS – and mortem AIDP case involving a 21-year-old Cau-
they concluded that the spinal roots were the focus casian woman. She died 14 days after the onset of
of the pathological effects of GBS. her symptoms and an autopsy was carried out 4 h
In 1969, Asbury carried out a clinicopathological later. Light microscopy showed scattered monocytic
study of the autopsied cases of 19 patients with idio- infiltration, and segmental demyelinative foci were
pathic polyneuropathy, and advocated that the most observed throughout the PNS. Electron microscopy
striking constant pathological finding was perivascu- of the myelinated fibers showed damaged myelin
lar mononuclear inflammatory infiltration of the sheaths with well-preserved axon cylinders. Some
whole peripheral nervous system, which includes totally denuded axons were also observed. In these
the spinal nerve roots to the terminal twigs in the lesions, some monocytes, which were morphologi-
muscle.14 They could not find abundant edematous cally consistent with macrophages, engulfed a large
changes in their cases, and suggested that the amount of myelin debris or penetrated the Schwann
inflammatory monocytes might play a direct role in cell basement membrane, pushing the Schwann cell
myelin destruction. bodies away from the myelin sheath. The most out-
In the present day, the demyelinative lesions of standing histological finding in this report was the
AIDP are considered to be patchily distributed “net-like or vesicular degeneration” at the surface of
throughout the PNS (Fig. 1). Because of this skipped the myelinated fibers with or without cellular

© 2016 Japanese Society for Neuroimmunology 313

Overview of the previous publications
Figure 2 The vagus nerve. Some almost intact myelinated fibers and
demyelinated fibers at the various degenerative phases. Scale bar,
10 lm. Reproduced from Nakano et al.30 with permission.
Figure 3 Demyelinating fiber. The outermost myelin lamellae are
stripped away by the cytoplasmic processes of the macrophage (arrow).
A, axon. Scale bar, 1 lm. Reproduced from Nakano et al.30 with permis-
sion.
invasion, in close proximity to fibers with an almost
intact appearance. Although these post-mortem find-
ings involving the peripheral nervous system speci-
mens might have been artifacts, they were
considered to be significant pathological changes.
314
Y. Nakano and T. Kanda
Figure 4 A completely denuded axon surrounded by macrophages
with a large amount of myelin debris, penetrating the Schwann cell
basal membrane. A, axon; M, macrophage; S, Schwann cell. Scale bar,
1 lm. Reproduced from Nakano et al.30 with permission.
In 1972, two important articles were reported.
Carpenter examined a post-mortem AIDP case of 47-
year-old man using light and electron microscopy.16
The patient, who died 18 days after the onset of
weakness, was autopsied at 4 h after his death. In
that report, mild perivascular inflammatory infiltra-
tion and demyelination without apparent axonal
degeneration was detected, mostly in the distal por-
tion of nerve roots and all of the sampled peripheral
nerves. At the demyelinative lesions, a constant fea-
ture was the subsistence of phagocytic cells with
myelin fragments underneath the Schwann cell
basement membrane. Myelin sheaths with vesicular
degeneration were also precisely described. The
outer myelin lamellae, separated at the interperiod
line, transformed into a series of vesicles. These vesi-
cles were formed by the splitting of the major dense
line and finally separating them from the ends of
the myelin sheaths.
An article by Prineas reported nine biopsy cases
and one autopsy case of AIDP.17 In six of the nine
biopsy specimens, active primary demyelination
associated with mononuclear cell invasion at the
internodes was detected. These monocytes invagi-
nated the Schwann cell basement membrane, dis-
placing the Schwann cell cytoplasm away from the
surrounding myelin sheath. In addition, the superfi-
cial myelin lamellae were stripped away at the
© 2016 Japanese Society for Neuroimmunology
Y. Nakano and T. Kanda
interperiod line by the cytoplasmic process of the
phagocytes, which contained a small number of
organelles in contrast with their cell body. Just two
biopsy cases showed vesicular degeneration. After
that report, 65 biopsy cases of GBS were reported by
Brechenmacher in 1987; with just eight cases pre-
senting vesicular degeneration.18 These authors
regarded vesicular degeneration, a rare pathological
change among biopsy cases, as an autopsy-related
artifact. These biopsy specimens showed only sparse
inflammatory infiltration.
In 1989, Kanda et al.19 documented a fulminant
case of AIDP. The patient died on the 8th day after
the onset of symptoms, and an autopsy was carried
out at 3 h after the patient’s death. Demyelination
with intact axons was observed throughout the
examined segments of the PNS with abundant
macrophages, in contrast to the lymphocytes, which
were scarce.
The process of demyelination in AIDP seemed to
be strongly affected by the penetration of mononu-
clear cells, probably macrophages rather than lym-
phocytes. They invade the Schwann cell basement
membrane and peel off the outer myelin lamellae
through a cytoplasmic process. Although the signifi-
cance of the vesicular degeneration remains contro-
versial, it might be the initial change of the
demyelination of AIDP.
What is the immunological target in AIDP?
The importance of mononuclear cells in the demyeli-
native process in AIDP gave rise to the need for the
precise discrimination of the profile of these cells,
and the detection of their accurate target by
immunohistochemistry.
In 1981, Nyland et al.20 carried out an immuno-
logical analysis of eight sural nerve biopsy specimens
from GBS patients. In acute cases in which the dura-
tion of symptoms was <12 weeks, only sparse
inflammatory cell infiltration was observed in the
endoneurium. In contrast, all of the chronic cases, in
which the duration was ≥12 weeks, showed signifi-
cant infiltration. The deposition of complement com-
ponent 3 (C3) was detected within the endoneurium
in four patients, and the deposition of immunoglob-
ulin G (IgG) and immunoglobulin M (IgM) was
found in two patients, mainly along the myelin
sheath.
Brechenmacher carried out immunohistochemical
examinations of 17 of their 65 biopsy cases, and
abnormal findings were observed in four specimens:
perivascular deposition of IgG or IgM and C3
© 2016 Japanese Society for Neuroimmunology
Overview of the previous publications
(n = 3), IgM deposition around the Schwann cell
surface (n = 1), and IgG deposition within the endo-
neurium (n = 1).18
In 1991, Honavar studied nine post-mortem GBS
patients.21 Frozen sections of the peripheral nerve
were available for immunological analysis in one
case. A striking increase in the numbers of leuko-
cytes (mainly T cells) and macrophages was seen in
both the endoneurium and the perineurium.
In 1996, a detailed immunohistochemical analysis
using well-preserved autopsy tissues from three
acute AIDP cases with clinical courses of 3, 8 and
9 days, respectively, were reported by Hafer-Macko
et al.22 In all three cases, the spinal roots were
found to be the most severely involved component
of the PNS. In the 3-day case, mild internodal
demyelination was found, and the infiltration of
lymphocytes and macrophages was sparse and pat-
chy. In contrast, both the 8-day and 9-day cases
showed severe demyelination and extensive infiltra-
tion by lymphocytes and macrophages. These
changes were more conspicuous in the 9-day case.
In the 3-day and 8-day cases, C3d and C5b-9 depos-
its were found on the outer surface of the Schwann
cells. The degree of deposition was less prominent
in the 9-day case. In comparison with their ultra-
structural findings, the C3d-immunostained fibers
corresponded to the fibers that presented vesicular
degeneration, and advanced demyelinated fibers
lacked C3d immunoreactivity. The macrophages
were mainly involved in the advanced demyelina-
tion; however, in the earlier stage of demyelination,
when the Schwann cells were encircled by C3d
immunoreactivity and presented outermost vesicular
degeneration, their participation was slight. Patho-
logical immunoreactivity against IgG or IgM was not
observed.
These pathological findings suggest that the tar-
get of AIDP is not the cytoplasm, but the plas-
malemma of the Schwann cells. In the presence of
lymphocytes, mainly T cells, the blood–nerve bar-
rier (BNB) was broken, and humoral factors
entered the PNS parenchyma. The binding of com-
plements to the outer surface of the Schwann cells
induced the vesicular degeneration of superficial
myelin lamellae. Finally, migrated macrophages
attacked the damaged myelin sheath, penetrated
the Schwann cell basement membrane, stripped
the outermost myelin lamellae at the interperiod
lines through their cytoplasmic process and acceler-
ated the demyelination. Throughout this demyeli-
native process, no specific antibodies were
detected.
315
Overview of the previous publications
Pathology of the axonal form of GBS (AMAN and
AMSAN)
Where are the lesions of the axonal form of GBS
located?
As described above, the classical pathological hall-
mark of GBS is conspicuous demyelination and vari-
ous degrees of inflammatory infiltration in the PNS.
Many authors have pointed out axonal degenera-
tion, often at the advanced demyelinated lesions,
but these changes have been thought to have
occurred as a result of secondary Wallerian degener-
ation.13,14
In 1986, Feasby et al.2 described five cases of
“acute axonal form of GBS.” A 64-year-old woman
with a 28-day clinical course was autopsied. In this
post-mortem case, severe axonal degeneration was
prominent in the spinal roots, especially the ventral
roots. The teased fiber examination of the peripheral
nerves showed that the axonal degeneration was
obvious and that demyelination was extremely rare.
Only a few scattered inflammatory infiltrates were
observed, and neither the perivascular cuffing of the
inflammatory cells nor endoneurial edematous
changes were found in the PNS. In the spinal cord,
the central chromatolysis was marked at the anterior
horn cells. The axonal changes were thought to be
primary pathological findings in these cases.
In 1995, Griffin et al.3 summarized 12 autopsied
GBS cases in northern China, with three cases each
of AMAN, AMSAN and AIDP, and three unclassified
cases. In that report, both the AMAN and AMSAN
cases had common pathological features: prominent
axonal degeneration with almost intact myelin
sheaths throughout the PNS, which was relatively
prominent in the spinal roots; a paucity of inflam-
matory lymphocytic infiltration; and the presence of
macrophages within the periaxonal spaces. These
histological features were completely different from
those of the classical GBS form, AIDP, which were
consistent with macrophage-mediated inflammatory
demyelinative disease.
In 1997, Sobue et al.6 reported 15 autopsied cases
of GBS. On the basis of the quantitative assessment
of teased fibers, primary axonal degeneration was
shown in five of 15 cases, which lacked evidence of
obvious segmental demyelination. Central chroma-
tolysis was frequently detected in these five cases,
and was rather prominent in comparison with the
other 10.
The periaxonal macrophages without destruction
of the surrounding myelin sheath, which were never
detected in AIDP, were pathological findings that
316
Y. Nakano and T. Kanda
were unique to AMAN and AMSAN.3–5 From this
point of view, five of the 65 cases reported by
Brechenmacher18 and one of the nine cases reported
by Honavar21 showed the pathological features asso-
ciated with the axonal form of GBS. Thus, in retro-
spect, these cases might be consistent with the
axonal type. The paucity of reports from Europe and
North America is partly derived from the different
prevalence. In North America and Europe, only
approximately 5% of the cases of clinically-diag-
nosed GBS correspond to the axonal form;23 in con-
trast, 30–47% of the cases in northern China, Japan,
Central America and South America correspond to
the axonal form.24–27
How does axonal degeneration occur in the axonal
form of GBS?
The periaxonal macrophages are suspected to play
an important role in the process of axonal degenera-
tion in AMAN and AMSAN. In 1996, Griffin et al.4
published two consecutive reports on autopsied cases
of axonal-form GBS. One of these reports dealt with
four AMSAN cases. All four patients presented pri-
mary axonal damage, and lacked intensive lympho-
cytic infiltration and showed macrophage invasion
in the periaxonal space, sometimes even to the
intra-axoplasm (Fig. 5). In addition, the nodes of
Ranvier of the myelinated nerve fibers were
enlarged, and some were overlaid by macrophages.
It was prompted that macrophages entered the peri-
axonal space from the nodes of Ranvier.
The study involved seven AMAN autopsied cases,
including three with extensive motor fiber degenera-
tion and four with mild pathological changes of the
motor nerve fibers.5 To argue the relationships
between the macrophages and the nodes of Ranvier,
they focused on estimating the nodal changes. In
the early phase of axonal degeneration, the main
pathological findings were the lengthening of the
nodes of Ranvier, where the axoplasm seemed to be
somewhat dense or cloudy, and sometimes swollen.
Occasionally, macrophages were observed to overlie
the nodes of Ranvier. Electron microscopy showed
that these macrophages extended their cytoplasmic
process through the Schwann cell basal lamina over
the nodes and came close to the axolemma. The
axolemma usually had a consecutive dense under-
coating beneath it, but that structure was observed
to be intermittent in the affected portion. In the
advanced phase, the macrophages invaded the peri-
axonal space, and separated the myelin terminal
loops from the axonal surface. It was difficult to
© 2016 Japanese Society for Neuroimmunology
Y. Nakano and T. Kanda Overview of the previous publications

(a) (b)

(c) (d)

(e) (f)

Figure 5 The axonal form of Guillain–Barr
e

syndrome. (a,b) Myelin ovoids are seen, while
macrophages have invaded the periaxonal
space of some myelinated fibers (arrows). (c–f)
Periaxonal macrophages and axons showing
various degrees of axonal degeneration. A,
axon; M, macrophage. Reproduced from Griffin
et al.4 with permission.

detect the axolemma to which the macrophages

were attached, in contrast to the adjacent well-pre-
served plasmalemma of the macrophages. Finally,
the axon collapsed and the Wallerian degeneration
rapidly progressed.
According to these observations, the macrophages
approached the nodes of Ranvier and passed
through the Schwann cell basal membrane to the
axonal surface. Subsequently, the macrophages
moved into the periaxonal space, dissecting the mye-
lin lateral loops and attached to the axon, where
they induced the axonal breakdown.
What is the immunological target in the axonal form of
GBS?
Several immunological analyses have been actively
carried out to clarify the event that triggers the
adhesion of macrophages to the axolemma. Sobue
et al.6 also reported that the macrophage invasion
was marked in the ventral roots in the axonal form
of GBS, whereas the T cell lymphocytic infiltration
to the PNS was intensive in AIDP cases. In 1996,
Hafer-Macko et al.7 carried out an immunohisto-
chemical investigation of seven AMAN cases. In all

© 2016 Japanese Society for Neuroimmunology 317

Overview of the previous publications
of them, primary axonal degeneration was con-
firmed, and the lengthened nodes of Ranvier and
periaxonal macrophages were present. The axo-
lemma at the nodes of Ranvier was strongly stained
by the complement activation product, C3d. These
nodes were mostly enlarged. The internodal axo-
lemma also showed intense immunoreactivity with
the terminal complement complex, C5b-9 and IgG,
but not IgM. The immunoreactivity tended to
become weakened, according to the progress of the
axonal degeneration. Through these observations,
the binding of the complements and immunoglobu-
lin, presumably IgG, to the surface of the internodal
axolemma was the initial event of the axonal disin-
tegrative process.
The humoral factors, including immunoglobulin
and complements, attacked the PNS, mainly at the
spinal roots, where the BNB was physiologically vul-
nerable, and these agents bound to the internodal
axolemma. The macrophages attached to the dam-
aged axolemma, penetrated the Schwann cell base-
ment membrane, and invaginated the periaxonal
space. Eventually, the consequential axonal damage
progressed into Wallerian degeneration.
Future directions
GBS is composed of two distinct disease entities:
AIDP and the axonal form of GBS. The pathologi-
cally significant feature of AIDP is the complement–
macrophage-induced cytotoxic damage on the plas-
malemma of the Schwann cells, whereas that of the
latter is the antibody–complement-mediated
immune attack on the axolemma at the nodes of
Ranvier. The development of novel therapies for
GBS is highly expected based on these two patholog-
ical mechanisms. However, we now consider the
upstream site of pathogenesis, BNB, to be more
important for overcoming this disorder. For this pur-
pose, we have established human peripheral nerve
microvascular endothelial and pericyte cell lines to
construct an in vitro model of BNB.28,29 Through
these efforts, we hope that GBS will be successfully
treated in the near future.
Conflict of interest
None declared.
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