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 Abstract
acute inflammatory demyelinating polyradicu- Guillain–Barr
e syndrome (GBS), a disease affecting the peripheral nervous
loneuropathy; acute motor and sensory axonal
system, is now well known. However, the disease concept has evolved over
neuropathy; acute motor axonal neuropathy;
successive periods. For example, for approximately nine decades from the
Guillain–Barr

e syndrome; pathology
first report of GBS, it was considered to have a spinal cord origin. After the
Correspondence first clinical report, the accumulation of detailed clinicopathological data
Takashi Kanda, MD, PhD, Department of Neu- showed that GBS is composed of two distinct clinicopathological entities:
rology and Clinical Neuroscience, Yamaguchi acute inflammatory demyelinating polyneuropathy, and acute motor axonal
University Graduate School of Medicine, 1-1-1 neuropathy or acute motor and sensory axonal neuropathy. Acute inflam-
Minamikogushi, Ube, Yamaguchi 755-8505,
matory demyelinating polyneuropathy is characterized by the patchy distri-
Japan.
bution of demyelinative foci throughout the peripheral nervous system,
Tel: +81-836-22-2714
Fax: +81-836-22-2364 whereas acute motor axonal neuropathy/acute motor and sensory axonal
Email: tkanda@yamaguchi-u.ac.jp neuropathy shows primary axonal degeneration in the peripheral nervous
system, which is particularly accentuated at the spinal nerve roots. The pur-
Received: 15 September 2016; revised: pose of the present article was to provide an overview of the previous pub-
26 September 2016; accepted: 26 September lications regarding the pathology of GBS and to thereby elucidate the
2016.
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
and immunohistochemical approaches6,7 supported
Guillain–Barr
e syndrome (GBS) is now a well- the presence of primary axonal degeneration. Now
known disorder of the peripheral nervous system the disease concept of the axonal form of GBS has
(PNS). Nevertheless, for approximately nine decades been established: namely, acute motor or motor and
from the first report of GBS, the disease was consid- sensory axonal neuropathy (AMAN and AMSAN).
ered to have a spinal cord origin.1 The aim of the present article was to provide an
Since the first clinical report, the accumulation of overview of the previous publications on the pathol-
detailed clinicopathological data has shown that the ogy of GBS and to thereby elucidate the pathological
classical form of GBS was primary inflammatory mechanisms underlying this still threatening disor-
demyelinative peripheral neuropathy. Consequently, der.
GBS was recognized as “acute inflammatory
demyelinating polyneuropathy (AIDP).”
Pathology of AIDP
In 1986, the concept of the axonal type of GBS
was proposed.2 It evoked controversy at the time, Where are the lesions of AIDP located?
chiefly because the axonal damage of the myelinated GBS became widely known to the world through a
fibers might have occurred as a result of Wallerian clinical report that was published in 1916, in which
degeneration because of intense inflammatory 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 Y. Nakano and T. Kanda

Figure 2 The vagus nerve. Some almost intact myelinated fibers and Figure 4 A completely denuded axon surrounded by macrophages
demyelinated fibers at the various degenerative phases. Scale bar, with a large amount of myelin debris, penetrating the Schwann cell
10 lm. Reproduced from Nakano et al.30 with permission. 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
Figure 3 Demyelinating fiber. The outermost myelin lamellae are the myelin sheaths.
stripped away by the cytoplasmic processes of the macrophage (arrow). An article by Prineas reported nine biopsy cases
A, axon. Scale bar, 1 lm. Reproduced from Nakano et al.30 with permis- and one autopsy case of AIDP.17 In six of the nine
sion. biopsy specimens, active primary demyelination
associated with mononuclear cell invasion at the
invasion, in close proximity to fibers with an almost internodes was detected. These monocytes invagi-
intact appearance. Although these post-mortem find- nated the Schwann cell basement membrane, dis-
ings involving the peripheral nervous system speci- placing the Schwann cell cytoplasm away from the
mens might have been artifacts, they were surrounding myelin sheath. In addition, the superfi-
considered to be significant pathological changes. cial myelin lamellae were stripped away at the

314 © 2016 Japanese Society for Neuroimmunology

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

interperiod line by the cytoplasmic process of the (n = 3), IgM deposition around the Schwann cell
phagocytes, which contained a small number of surface (n = 1), and IgG deposition within the endo-
organelles in contrast with their cell body. Just two neurium (n = 1).18
biopsy cases showed vesicular degeneration. After In 1991, Honavar studied nine post-mortem GBS
that report, 65 biopsy cases of GBS were reported by patients.21 Frozen sections of the peripheral nerve
Brechenmacher in 1987; with just eight cases pre- were available for immunological analysis in one
senting vesicular degeneration.18 These authors case. A striking increase in the numbers of leuko-
regarded vesicular degeneration, a rare pathological cytes (mainly T cells) and macrophages was seen in
change among biopsy cases, as an autopsy-related both the endoneurium and the perineurium.
artifact. These biopsy specimens showed only sparse In 1996, a detailed immunohistochemical analysis
inflammatory infiltration. using well-preserved autopsy tissues from three
In 1989, Kanda et al.19 documented a fulminant acute AIDP cases with clinical courses of 3, 8 and
case of AIDP. The patient died on the 8th day after 9 days, respectively, were reported by Hafer-Macko
the onset of symptoms, and an autopsy was carried et al.22 In all three cases, the spinal roots were
out at 3 h after the patient’s death. Demyelination found to be the most severely involved component
with intact axons was observed throughout the of the PNS. In the 3-day case, mild internodal
examined segments of the PNS with abundant demyelination was found, and the infiltration of
macrophages, in contrast to the lymphocytes, which lymphocytes and macrophages was sparse and pat-
were scarce. chy. In contrast, both the 8-day and 9-day cases
The process of demyelination in AIDP seemed to showed severe demyelination and extensive infiltra-
be strongly affected by the penetration of mononu- tion by lymphocytes and macrophages. These
clear cells, probably macrophages rather than lym- changes were more conspicuous in the 9-day case.
phocytes. They invade the Schwann cell basement In the 3-day and 8-day cases, C3d and C5b-9 depos-
membrane and peel off the outer myelin lamellae its were found on the outer surface of the Schwann
through a cytoplasmic process. Although the signifi- cells. The degree of deposition was less prominent
cance of the vesicular degeneration remains contro- in the 9-day case. In comparison with their ultra-
versial, it might be the initial change of the structural findings, the C3d-immunostained fibers
demyelination of AIDP. corresponded to the fibers that presented vesicular
degeneration, and advanced demyelinated fibers
lacked C3d immunoreactivity. The macrophages
What is the immunological target in AIDP?
were mainly involved in the advanced demyelina-
The importance of mononuclear cells in the demyeli- tion; however, in the earlier stage of demyelination,
native process in AIDP gave rise to the need for the when the Schwann cells were encircled by C3d
precise discrimination of the profile of these cells, immunoreactivity and presented outermost vesicular
and the detection of their accurate target by degeneration, their participation was slight. Patho-
immunohistochemistry. logical immunoreactivity against IgG or IgM was not
In 1981, Nyland et al.20 carried out an immuno- observed.
logical analysis of eight sural nerve biopsy specimens These pathological findings suggest that the tar-
from GBS patients. In acute cases in which the dura- get of AIDP is not the cytoplasm, but the plas-
tion of symptoms was <12 weeks, only sparse malemma of the Schwann cells. In the presence of
inflammatory cell infiltration was observed in the lymphocytes, mainly T cells, the blood–nerve bar-
endoneurium. In contrast, all of the chronic cases, in rier (BNB) was broken, and humoral factors
which the duration was ≥12 weeks, showed signifi- entered the PNS parenchyma. The binding of com-
cant infiltration. The deposition of complement com- plements to the outer surface of the Schwann cells
ponent 3 (C3) was detected within the endoneurium induced the vesicular degeneration of superficial
in four patients, and the deposition of immunoglob- myelin lamellae. Finally, migrated macrophages
ulin G (IgG) and immunoglobulin M (IgM) was attacked the damaged myelin sheath, penetrated
found in two patients, mainly along the myelin the Schwann cell basement membrane, stripped
sheath. the outermost myelin lamellae at the interperiod
Brechenmacher carried out immunohistochemical lines through their cytoplasmic process and acceler-
examinations of 17 of their 65 biopsy cases, and ated the demyelination. Throughout this demyeli-
abnormal findings were observed in four specimens: native process, no specific antibodies were
perivascular deposition of IgG or IgM and C3 detected.

© 2016 Japanese Society for Neuroimmunology 315

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

were unique to AMAN and AMSAN.3–5 From this

Pathology of the axonal form of GBS (AMAN and
point of view, five of the 65 cases reported by
AMSAN)
Brechenmacher18 and one of the nine cases reported
Where are the lesions of the axonal form of GBS by Honavar21 showed the pathological features asso-
located? ciated with the axonal form of GBS. Thus, in retro-
As described above, the classical pathological hall- spect, these cases might be consistent with the
mark of GBS is conspicuous demyelination and vari- axonal type. The paucity of reports from Europe and
ous degrees of inflammatory infiltration in the PNS. North America is partly derived from the different
Many authors have pointed out axonal degenera- prevalence. In North America and Europe, only
tion, often at the advanced demyelinated lesions, approximately 5% of the cases of clinically-diag-
but these changes have been thought to have nosed GBS correspond to the axonal form;23 in con-
occurred as a result of secondary Wallerian degener- trast, 30–47% of the cases in northern China, Japan,
ation.13,14 Central America and South America correspond to
In 1986, Feasby et al.2 described five cases of the axonal form.24–27
“acute axonal form of GBS.” A 64-year-old woman
with a 28-day clinical course was autopsied. In this
How does axonal degeneration occur in the axonal
post-mortem case, severe axonal degeneration was
form of GBS?
prominent in the spinal roots, especially the ventral
roots. The teased fiber examination of the peripheral The periaxonal macrophages are suspected to play
nerves showed that the axonal degeneration was an important role in the process of axonal degenera-
obvious and that demyelination was extremely rare. tion in AMAN and AMSAN. In 1996, Griffin et al.4
Only a few scattered inflammatory infiltrates were published two consecutive reports on autopsied cases
observed, and neither the perivascular cuffing of the of axonal-form GBS. One of these reports dealt with
inflammatory cells nor endoneurial edematous four AMSAN cases. All four patients presented pri-
changes were found in the PNS. In the spinal cord, mary axonal damage, and lacked intensive lympho-
the central chromatolysis was marked at the anterior cytic infiltration and showed macrophage invasion
horn cells. The axonal changes were thought to be in the periaxonal space, sometimes even to the
primary pathological findings in these cases. intra-axoplasm (Fig. 5). In addition, the nodes of
In 1995, Griffin et al.3 summarized 12 autopsied Ranvier of the myelinated nerve fibers were
GBS cases in northern China, with three cases each enlarged, and some were overlaid by macrophages.
of AMAN, AMSAN and AIDP, and three unclassified It was prompted that macrophages entered the peri-
cases. In that report, both the AMAN and AMSAN axonal space from the nodes of Ranvier.
cases had common pathological features: prominent The study involved seven AMAN autopsied cases,
axonal degeneration with almost intact myelin including three with extensive motor fiber degenera-
sheaths throughout the PNS, which was relatively tion and four with mild pathological changes of the
prominent in the spinal roots; a paucity of inflam- motor nerve fibers.5 To argue the relationships
matory lymphocytic infiltration; and the presence of between the macrophages and the nodes of Ranvier,
macrophages within the periaxonal spaces. These they focused on estimating the nodal changes. In
histological features were completely different from the early phase of axonal degeneration, the main
those of the classical GBS form, AIDP, which were pathological findings were the lengthening of the
consistent with macrophage-mediated inflammatory nodes of Ranvier, where the axoplasm seemed to be
demyelinative disease. somewhat dense or cloudy, and sometimes swollen.
In 1997, Sobue et al.6 reported 15 autopsied cases Occasionally, macrophages were observed to overlie
of GBS. On the basis of the quantitative assessment the nodes of Ranvier. Electron microscopy showed
of teased fibers, primary axonal degeneration was that these macrophages extended their cytoplasmic
shown in five of 15 cases, which lacked evidence of process through the Schwann cell basal lamina over
obvious segmental demyelination. Central chroma- the nodes and came close to the axolemma. The
tolysis was frequently detected in these five cases, axolemma usually had a consecutive dense under-
and was rather prominent in comparison with the coating beneath it, but that structure was observed
other 10. to be intermittent in the affected portion. In the
The periaxonal macrophages without destruction advanced phase, the macrophages invaded the peri-
of the surrounding myelin sheath, which were never axonal space, and separated the myelin terminal
detected in AIDP, were pathological findings that loops from the axonal surface. It was difficult to

316 © 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

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

© 2016 Japanese Society for Neuroimmunology 317

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

of them, primary axonal degeneration was con- 2. Feasby TE, Gilbert JJ, Brown WF, et al. An acute axonal
firmed, and the lengthened nodes of Ranvier and form of Guillain-Barr
e polyneuropathy. Brain. 1986; 109:
periaxonal macrophages were present. The axo- 1115–26.
lemma at the nodes of Ranvier was strongly stained 3. Griffin JW, Li CY, Ho TW, et al. Guillain-Barr
e syndrome
by the complement activation product, C3d. These in northern China. The spectrum of neuropathological
nodes were mostly enlarged. The internodal axo- changes in clinically defined cases. Brain. 1995; 118:
lemma also showed intense immunoreactivity with 577–95.
the terminal complement complex, C5b-9 and IgG, 4. Griffin JW, Li CY, Ho TW, et al. Pathology of the motor-
sensory axonal Guillain-Barr
e syndrome. Ann Neurol.
but not IgM. The immunoreactivity tended to
1996; 39: 17–28.
become weakened, according to the progress of the
5. Griffin JW, Li CY, Macko C, et al. Early nodal changes in
axonal degeneration. Through these observations,
the acute motor axonal neuropathy pattern of the Guil-
the binding of the complements and immunoglobu-
lain-Barr
e syndrome. J Neurocytol. 1996; 25: 33–51.
lin, presumably IgG, to the surface of the internodal
6. Sobue G, Li M, Terao S, et al. Axonal pathology in Japa-
axolemma was the initial event of the axonal disin- nese Guillain-Barr
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tegrative process. cases. Neurology. 1997; 48: 1694–700.
The humoral factors, including immunoglobulin 7. Hafer-Macko C, Hsieh ST, Li CY, et al. Acute motor axo-
and complements, attacked the PNS, mainly at the nal neuropathy: an antibody-mediated attack on axo-
spinal roots, where the BNB was physiologically vul- lemma. Ann Neurol. 1996; 40: 635–44.
nerable, and these agents bound to the internodal 8. Guillain G, Barr
e JA, Strohl A. Sur un syndrome de
axolemma. The macrophages attached to the dam- radiculon
evrite avec hyperalbuminose du liquide
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ephalo-rachidien sans r
eaction cellulaire: remarques
ment membrane, and invaginated the periaxonal surles caracteres cliniques et graphiques des r
eflexes
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ed Ho ^p Paris. 1916; 40: 1462–70.
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aigu€e. Arch Physiol. 1876; 8: 312–7.
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Conflict of interest
lain-Barr
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None declared. eral nerve in 65 patients. Clin Neuropathol. 1987; 6:
19–24.
19. Kanda T, Hayashi H, Tanabe H, et al. A fulminant case of
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