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Anti-sulfatide antibodies in peripheral neuropathy

Authors:

Abstract

A study was carried out on 135 patients with chronic idiopathic neuropathy (63), neuropathy associated with monoclonal gammopathy (51, including eight with anti-MAG antibody activity) and the Guillain-Barré syndrome (GBS) (21). Serum IgM, IgG and IgA anti-sulphatide antibody titres were compared with titres in 304 patients with other neurological or immunological diseases and in 50 normal subjects. Titres were presented a) as the highest serum dilution at which reactivity could be detected, and b) in the linear region of the optical density curve. A substantial number of patients with neurological or immunological diseases had higher titres than normal subjects. Compared with normal and disease controls, five patients with neuropathy associated with IgMk monoclonal gammopathy had raised titres of IgM anti-sulphatide antibodies and one patient with GBS had raised IgM, IgG and IgA anti-sulphatide antibodies in the acute phase of the disease. Two patients had a predominantly axonal sensory neuropathy with presenting symptoms of painful paresthesiae and minimal neurological deficit. Three patients had a predominantly demyelinating sensorimotor neuropathy associated with anti-MAG antibody activity. The patient with GBS had extensive sensory loss and antibody titres returned to normal within three weeks. Raised titres of anti-sulphatide antibodies occurred in several types of neuropathy, but all had some degree of sensory impairment and associated immunological abnormality.
1ournal
of
Neurology,
Neurosurgery,
and
Psychiatry
1993;56:1
164-1168
Anti-sulphatide
antibodies
in
peripheral
neuropathy
L
H
van
den
Berg,
C
L
A
M
Lankamp,
A
E
J
de
Jager,
N
C
Notermans,
P
Sodaar,
J
Marrink,
H
J
de
Jong,
P
R
Bar,
J
H
J
Wokke
University
Hospital,
Utrecht,
The
Netherlands
Department
of
Neurology
L
H
van
den
Berg
C
L
A
M
Lankamp
N
C
Notermans
P
Sodaar
P
R
Bar
J
H
J
Wokke
University
Hospital,
Grongingen,
The
Netherlands
Department
of
Neurology
A
E
J
de
Jager
Department
of
Internal
Medicine
J
Marrink
H
J
de
Jong
Correspondence
to:
Dr
van
den
Berg,
Department
of
Neurology,
University
Hospital
Utrecht,
PO
Box
85500,
3508
GA
Utrecht,
The
Netherlands.
Received
9
July
1992
and
in
revised
form
28
October
1992.
Accepted
28
October
1992
Abstract
A
study
was
carried
out
on
135
patients
with
chronic
idiopathic
neuropathy
(63),
neuropathy
associated
with
monoclonal
gammopathy
(51,
including
eight
with
anti-MAG
antibody
activity)
and
the
Guillain-Barre
syndrome
(GBS)
(21).
Serum
IgM,
IgG
and
IgA
anti-sulphatide
antibody
titres
were
compared
with
titres
in
304
patients
with
other
neurological
or
immunological
diseases
and
in
50
normal
subjects.
Titres
were
presented
a)
as
the
highest
serum
dilution
at
which
reactiv-
ity
could
be
detected,
and
b)
in
the
linear
region
of
the
optical
density
curve.
A
substantial
number
of
patients
with
neu-
rological
or
immunological
diseases
had
higher
titres
than
normal
subjects.
Compared
with
normal
and
disease
controls,
five
patients
with
neuropathy
associated
with
IgMk
monoclonal
gam-
mopathy
had
raised
titres
of
IgM
anti-
sulphatide
antibodies
and
one
patient
with
GBS
had
raised
IgM,
IgG
and
IgA
anti-sulphatide
antibodies
in
the
acute
phase
of
the
disease.
Two
patients
had
a
predominantly
axonal
sensory
neuro-
pathy
with
presenting
symptoms
of
painful
paresthesiae
and
minimal
neuro-
logical
deficit.
Three
patients
had
a
pre-
dominantly
demyelinating
sensorimotor
neuropathy
associated
with
anti-MAG
antibody
activity.
The
patient
with
GBS
had
extensive
sensory
loss
and
antibody
titres
returned
to
normal
within
three
weeks.
Raised
titres
of
anti-sulphatide
antibodies
occurred
in
several
types
of
neuropathy,
but
all
had
some
degree
of
sensory
impairment
and
associated
immunological
abnormality.
(7
Neurol
Neurosurg
Psychiatry
1993;56:
1164-1168)
Raised
titres
of
serum
anti-sulphatide
anti-
bodies
were
initially
reported
in
patients
with
multiple
sclerosis,
idiopathic
thrombocy-
topaenic
purpura
and
chronic
active
hepatitis.
1-3
Recently,
these
antibodies
have
been
found
in
predominantly
sensory
axonal
neuropathy,
demyelinating
neuropathy
asso-
ciated
with
anti-MAG
antibodies
and
also
in
the
Guillain-Barre
syndrome
(GBS).s7
To
define
which
subtypes
of
peripheral
neuropathy
are
associated
with
raised
anti-
sulphatide
antibodies,
we
studied
patients
with
neuropathy
and
other
neurological
and
immunological
diseases,
and
normal
subjects.
MATERIALS
AND
METHODS
Patients
Included
in
the
study
were
135
patients
with
chronic
idiopathic
axonal
polyneuropathy-
CIAP
[sensory
(26),
sensorimotor
(35),
motor
(2)],
neuropathy
associated
with
mono-
clonal
gammopathy
[IgM
(19,
including
eight
with
anti-MAG
antibody
activity),
IgG
(28),
IgA
(4)]
and
GBS
(21).8
All
patients
were
diagnosed
by
clinical,
electrophysiological
and
laboratory
examination
at
the
Departments
of
Neurology
of
the
University
Hospitals
of
Utrecht
and
Groningen.''0
Controls
included
patients
with
various
other
neuropathies
(vitamin
B
deficiency
(4),
diabetes
mellitus
(6),
Sj6gren's
syndrome
(1),
and
paraneoplastic
(3)
and
hereditary
(6)
neuropathy),
motor
neuron
disease
(36;
including
21
with
classical
amyotrophic
lat-
eral
sclerosis
and
15
with
lower
motor
neuron
disease),
multiple
sclerosis
(20),
myasthenia
gravis
(20),
as
well
as
other
neurological
dis-
eases
(OND
(100);
including
Alzheimer's
disease
(20),
Parkinson's
disease
(20),
stroke
(20),
epilepsy
(20),
head
trauma
(20)),
other
immunological
diseases
(OID
(48);
including
rheumatoid
arthritis
(18),
systemic
lupus
ery-
thematosus
without
neurological
symptoms
(20),
chronic
active
hepatitis
(7),
Sj6gren's
syndrome
(3)),
monoclonal
gammopathy
without
neurological
disease
(MGWND;
IgM
(20),
IgG
(20),
IgA
(20))
and
normal
sub-
jects
(50).
Serum
was
obtained
from
all
patient
and
control
groups
and
stored
at
-70°C
until
use.
ANTI-SULPHATIDE
ANTIBODY
ASSAY
Anti-sulphatide
antibodies
were
measured
by
enzyme-linked
immunosorbent
assay
(ELISA),
as
previously
described.10
Briefly,
microwells
were
coated
with
50
pl
of
methanol
containing
5
,ug/ml
of
sulphatide
(Sigma)
and
evaporated
overnight.
Uncoated
microwells
were
used
as
controls.
Wells
were
saturated
with
100
,ul
of
PBS
buffer
(0
15
M
NaCl,
0-01
M
NaH,P04,
pH
7A4)
containing
1%
BSA
(ELISA
solution)
for
four
hours.
Serum
serially
diluted
in
50
pul
of
ELISA
solution
beginning
with
a
dilution
of
1:200
was
added
in
triplicate
to
sulphatide-coated
wells
and
uncoated
control
wells,
and
incubated
overnight
at
4°C.
After
washing,
peroxidase-conjugated
rabbit
antibodies
to
human
IgM,
IgG,
IgA,
kappa
or
lambda
light
chains
(Sigma),
diluted
1:1000
in
ELISA
solution
were
added
for
two
hours.
Reaction
products
were
visualised
with
0-phenylene-
1164
group.bmj.com on July 15, 2011 - Published by jnnp.bmj.comDownloaded from
Anti-sulphatide
antibodies
in
peripheral
neuropathy
Figure
A
(top):
IgM
anti-
sulphatide
antibody
titres
determined
by
method
A.
Lower
horizontal
line
represents
the
highest
titre
of
normal
controls.
Upper
horizontal
line
represents
the
highest
titre
of
disease
controls;
B
(bottom):
IgM
anti-sulphatide
antibody
activity
in
Arbitrary
Units
per
litre
(AUll)
determined
by
method
B.
Lower
horizontal
line
represents
the
highest
antibody
titre
(490)
as
well
as
the
mean
value
plus
3
SD
of
normal
controls
(493).
Dotted
line
represents
the
mean
value
plus
3
SD
of
normal
and
disease
controls
(952).
Upper
horizontal
line
represents
the
highest
antibody
titre
of
disease
controls.
NORM
=
nornal
subjects;
OND
=
other
neurological
diseases;
MND
=
motor
neuron
disease;
MG
=
myasthenia
gravis;
MS
=
multiple
sclerosis;
OID
=
other
immunological
disease;
MGWND
=
monoclonal
gammopathy
without
neurological
disease;
VN
=
various
neuropathies;
IN
=
idiopathic
neuropathies;
NAMG
=
neuropathy
associated
with
monoclonal
gammopathy;
GBS
=
Guillain
Barre
Syndrome.
Numbers
given
along
the
X-axis
represent
numbers
of
patients
with
values
of
0.
>
12800
6400
3200
1600
800
400
200
(0)
A
f%^f%
B
..
....
...
...
..
......:
....
*~~~~~~~~..
....
......
(17)
(53)
(
11)
(2)
(5)
(
11)
(6)
(6)
(32)
(1
8)
(4)
NORM
OND
MND
MG
MS
OID
MGWND
VN
IN
NAMG
GBS
2UUU
2000
1800
1600
1400
1200
1000_--_
_
800
600
400
*
.
*
.
.*
:
200
.z.
@.-.....
..
*---*------..
*..
*:::-
..
:
.....
:*:
(0)
* .
.*.
...
......
..............
(7)
(
18)
(2)
(2)
(2)
(8)
(2)
(3)
(9)
(9)
(2)
NORM
OND
MND
MG
MS
OID
MGWND
VN
IN
NAMG
GBS
diamine
as
substrate
and
read
spectrophoto-
metrically
at
492
nm
in
a
multiscan
reader
(Bio-Rad).
DETERMINATION
OF
ANTIBODY
TITRES
Anti-sulphatide
antibody
titres
were
pre-
sented
in
two
ways
to
increase
the
validity
of
abnormal
results
and
for
better
comparison
with
previously
reported
anti-sulphatide
anti-
body
titres4:
A)
Readings
were
taken
from
the
last
part
of
the
optical
density
(OD)
curve.
For
each
patient
the
titre
was
taken
as
the
highest
serum
dilution
at
which
spectrophotometric
optical
density
readings
for
sulphatide-coated
wells
were
0
05
units
greater
than
in
corres-
ponding
uncoated
control
wells.
B)
Readings
were
also
taken
from
the
lin-
ear
region
of
the
OD
curve
as
previously
described.10
Serum
of
a
patient
with
high
titre
of
anti-sulphatide
antibodies
was
used
as
an
internal
control
sample
in
each
experiment
and
all
test
sera
were
normalised
against
it.
The
binding
of
this
serum
was
given
the
value
of
10-000
Arbitrary
Units
per
litre
(AU/1).
Antibody
titres
were
determined
as
the
rela-
tive
level
of
immunoglobulin
binding
com-
pared
to
this
positive
control.
Values
in
uncoated
control
wells
were
subtracted
from
values
in
sulphatide-coated
wells.
DETECTION
OF
ANTI-MAG
ANTIBODIES
Anti-MAG
antibodies
were
measured
in
all
patients
with
peripheral
neuropathy
by
ELISA
using
sulphated
glucuronic
acid
para-
globoside
(SGPG)
as
antigen
(kindly
pro-
vided
by
Dr
N
Latov,
Columbia
University,
New
York),
as
previously
described."'
Anti-
MAG
antibody
activity
was
confirmed
in
patients
with
high
titres
by
Western
Blot
after
separation
of
myelin
proteins
by
SDS-PAGE
as
described
previously.'2
ABSORPTION
OF
PATIENT
SERA
Serum
from
patients
who
had
raised
anti-
MAG
and
anti-sulphatide
antibodies
was
absorbed
with
sulphatide
by
the
method
of
Hirabayashi
et
al.313
Briefly,
sulphatide
was
conjugated
with
Octyl-Sepharose
4B
beads,
suspended
in
patient
serum
at
various
dilu-
tions
and
left
overnight
at
4°C.
The
mixture
was
centrifuged
for
5
minutes
at
1000
rpm
to
remove
the
Sepharose
beads
and
the
remaining
antibody
activity
of
the
supernantant
was
measured
by
ELISA
and
1165
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van
den
Berg,
Lankamp,
de
Jager,
Notermans,
Sodaar,
Marrink,
de
long,
Bar,
Wokke
Table
Clinicalfeatures
of
patients
with
raised
anti-sulphatide
antibody
titres.
Diagnosis
Anti-sulfatide
Patient
Disease
Electro-
number
AgelSex
Neurologic
Immunologic
Duration
Clinical
features
physiol
IgM
IgG
IgA
Al
61/M
Sensory
WM:
IgMk
8
year
Numbness,
nocturnal
paresthesia
in
A
51200/
-
-
neuropathy
LEs.
Impairment
of
all
sensory
4900
modalities
distally
in
LEs.
Normal
strength.
Reflexes
intact.
A2
68/M
Predominantly
NMG:
IgMk
23
year
Numbness,
painful
nocturnal
A
102400/
-
sensory
paresthesia
in
LEs.
Impairment
of
10000
neuropathy
all
sensory
modalities
distally
in
LEs,
impaired
vibratory
sensation
in
hands.
Weakness
distally
in
LEs
and
UEs
(MRC
5-).
Absent
DTRs
in
LEs.
BI
65/M
Sensorimotor
NMG:
IgMk
19
year
Numbness,
painful
nocturnal
cramps
D
+
A
12800/
neuropathy
anti-MAG
and
paresthesias
in
LEs
and
UEs.
1450
Impairment
of
all
sensory
modalities
distally
in
LEs
and
UEs.
Weakness
distally
in
LEs
(MRC
3).
Absent
DTRs
in
LEs
and
UTEs.
B2
83/M
Sensorimotor
NMG:
IgMk
29
year
Numbness,
painful
paresthesia
in
LEs
D
51200/
neuropathy
anti-MAG
and
UEs.
Impairment
of
all
sensory
3500
modalities
distally
in
LEs
and
UEs.
Weakness
in
LEs
(MRC
4).
Ataxia
in
LEs
and
UEs.
Tremor
in
UEs.
Absent
DTRs
in
LEs
and
UEs.
B3
69/M
Sensorimotor
NMG:
IgMk
11
year
Numbness,
paresthesia
in
LEs.
D
25600/
-
NR
neuropathy
anti-MAG
Impairment
of
all
sensory
modalities
2945
distally
in
LEs.
Weakness
in
LEs
(MRC
3).
Absent
DTRs
in
LEs.
C1
36/M
GBS
IgM
T
6
months
Numbness
in
LEs
and
UEs.
Impairment
D
12800/
6400/ 3200/
IgG
T
of
all
sensory
modalities
in
LEs
and
3122
640
984
IgA
T
UEs.
Weakness
in
LEs
(MRC
2)
and
LEs
(MRC
4).
Absent
DTRs
in
LEs
and
UEs.
M
=
male;
GBS
=
Guillain
Barre
Syndrome;
NMG
=
non-malignant
monoclonal
gammopathy;
WM
=
Waldenstrom
Macroglobulinaemia;
LEs
=
lower
extremities;
UEs
=
upper
extremities;
MRC
=
Medical
Research
Council;
DTRs
=
deep
tendon
reflexes;
D
=
demyelination;
A
=
axonal;
anti-sulphatide
=
anti-
sulphatide
antibody
titre:
method
A/method
B;
NR
=
not
raised.
compared
with
serum
absorbed
with
uncon-
jugated
Octyl-Sepharose
beads.
Patient
serum
with
raised
anti-MAG
antibodies
with-
out
anti-sulphatide
antibody
activity
served
as
a
control.
Results
ANTIBODY
ELISA
ASSAY
Serum
anti-sulphatide
antibodies
were
mea-
sured
by
ELISA
and
antibody
titres
were
pre-
sented
in
two
ways,
as
shown
in
fig
A
(method
A)
and
B
(method
B)
for
IgM
anti-
sulphatide
antibodies.
Method
A
IgM
anti-sulphatide
antibody
titres
in
normal
individuals
ranged
from
0
to
1600.
Ten
dis-
ease
controls
had
IgM
anti-sulphatide
anti-
body
titres
in
the
range
of
1600
to
6400.
This
range
was
considered
borderline,
not
specific
for
one
disease
or
syndrome.
IgM
anti-sul-
phatide
antibody
titres
of
greater
than
6400
were
thus
considered
raised,
and
were
only
seen
in
five
patients
with
neuropathy
associ-
ated
with
monoclonal
gammopathy
and
in
one
patient
with
GBS.
IgG
and
IgA
anti-sul-
phatide
antibody
titres
(not
shown)
were
gen-
erally
lower
than
IgM
and
ranged
from
0
to
800
for
IgG
and
from
0
to
400
for
IgA
in
nor-
mal
controls,
and
from
0
to
1600
for
IgG
and
from
0
to
800
for
IgA
in
disease
controls.
Anti-sulphatide
antibody
titres
greater
than
1600
for
IgG
and
greater
than
800
for
IgA
were
considered
raised
and
were
found
only
in
the
GBS
patient
who
also
had
raised
IgM
titres.
Method
B
Normal
controls
had
IgM
anti-sulphatide
antibody
activity
from
0
to
490
and
disease
controls
from
0
to
1950
AU/l
(fig
B).
Antibody
activity
of
greater
than
1950
AU/i
was
found
in
four
patients
with
neuropathy
associated
with
monoclonal
gammopathy
and
one
patient
with
GBS,
all
of
whom
had
raised
anti-sulphatide
antibodies
by
method
A
above.
IgG
and
IgA
antibody
activity
(not
shown)
ranged
from
0
to
292
for
IgG
and
0
to
83
AU/i
for
IgA
and
disease
controls
from
0
to
1518
for
IgG
and
0
to
750
AU/l
for
IgA.
All
patients
with
neuropathy
had
IgG
antibody
activity
in
the
range
of
disease
controls
and
only
the
patient
with
GBS
(previously
identi-
fied
by
method
A)
had
a
greater
antibody
activity
for
IgA.
Mean
value
plus
3
SD
of
controls
as
normal
range
To
compare
the
results
to
previously
pub-
lished
work4
we
determined
the
mean
value
plus
3
SD
for
normal
controls
by
method
B,
which
was
493
AU/l
for
IgM
anti-sulphatide
antibodies.
When
this
value
was
taken
as
the
upper
limit
of
normal,
11
patients
with
values
between
493
and
1950
AU/l
had
raised
anti-
body
activity,
of
which
eight
were
disease
controls.
The
GBS
patient
had
higher
anti-
body
activity
for
both
IgG
and
IgA,
but
also
seven
disease
controls
for
IgG
and
24
disease
controls
for
IgA.
We
also
determined
the
mean
value
plus
3
SD
of
normal
and
disease
controls,
which
was 952
AU/I
for
IgM
antibodies.
One
patient
with
neuropathy
associated
with
monoclonal
gammopathy
(also
positive
by
method
A)
and
two
disease
controls
had
anti-
body
activity
between
953
and
1950
AU/i.
1166
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Anti-sulphatide
antibodies
in
peripheral
neuropathy
The
GBS
patient
had
raised
antibody
activity
for
IgG
and
IgA.
PATIENTS
WITH
RAISED
ANTI-SULPHATIDE
ANTIBODIES
A
summary
of
the
clinical
and
laboratory
data
of
patients
with
raised
anti-sulphatide
anti-
bodies
is
presented
in
the
table.
Six
patients
had
raised
anti-sulphatide
antibodies
com-
pared
with
normal
and
disease
controls
by
method
A.
Five
of
them
also
had
raised
anti-
sulphatide
antibodies
compared
with
disease
controls
by
method
B,
and
one
of
them
(patient
B
1,
table)
had
raised
antibodies
com-
pared
with
the
mean
value
plus
3
SD
of
nor-
mal
and
disease
controls.
Three
clinical
presentations
were
associated
with
raised
anti-sulphatide
antibodies:
A)
Painful
sensory
neuropathy
Patients
Al
and
A2
had
identical
presenting
complaints
of
painful
nocturnal
paresthesiae.
Otherwise
neurological
deficit
was
minimal
and
the
clinical
course
was
very
slowly
pro-
gressive.
B)
Sensorimotor
neuropathy
associated
with
anti-MAG
antibody
activity
Three
out
of
eight
patients
with
neuropathy
associated
with
anti-MAG
antibody
activity
also
had
raised
titres
of
anti-sulphatide
anti-
bodies.
The
anti-MAG
and
anti-sulphatide
antibodies
were
of
the
IgMk
isotype
and
absorption
of
patient
serum
with
sulphatide
bound
to
Octyl-Sepharose
resulted
in
approx-
imately
80%
reduction
of
antibody
binding
to
sulphatide
as
well
as
to
MAG,
suggesting
that
the
IgMk
monoclonal
antibody
reacted
with
both
antigens.
As
control,
absorption
of
sera
with
anti-MAG
antibodies
without
anti-sul-
phatide
antibodies
did
not
reduce
antibody
binding
to
MAG.
C)
GBS
One
of
21
patients
with
GBS
had
raised
anti-
sulphatide
antibody
titres.
This
patient
had
raised
IgM,
IgG
and
IgA
anti-sulphatide
anti-
bodies
and
had
the
most
profound
sensory
loss
among
the
21
patients.
Detailed
clinical
data
of
the
21
GBS
patients
were
previously
published.10
Titres
were
highest
in
the
acute
phase
of
the
disease
and
returned
to
the
nor-
mal
range
within
three
weeks.
Discussion
A
substantial
number
of
patients
with
neuro-
logical
or
immunological
diseases
had
higher
anti-sulphatide
antibody
titres
compared
with
normal
subjects.
Six
patients
with
peripheral
neuropathy
had
raised
anti-sulphatide
anti-
bodies
compared
with
normal
and
disease
controls.
However,
neuropathy
associated
with
raised
anti-sulphatide
antibodies
does
not
appear
to
constitute
one
clinical
syn-
drome.
Two
patients
had
a
predominantly
axonal
sensory
neuropathy
with
presenting
symptoms
of
painful
paresthesiae
and
mini-
mal
neurological
deficit.
Three
patients
had
a
severe
sensorimotor
neuropathy
with
demyelination
and
raised
anti-MAG
anti-
bodies
and
one
patient
had
acute
GBS
with
extensive
sensory
loss.
The
chronic
neu-
ropathies
were
all
associated
with
IgM
mono-
clonal
gammopathy.
Absorbtion
studies
in
the
three
patients
with
raised
titres
of
anti-MAG
and
anti-sul-
phatide
antibodies
suggest
that
the
IgMk
monoclonal
gammopathy
has
antibody
activ-
ity
to
both
antigens.
Ilyas
et
al
reported
simi-
lar
results
in
two
of
ten
patients
with
anti-MAG
antibodies.5
By
using
thin-layer
chromotography
(TLC)
anti-sulphatide
antibodies
were
previ-
ously
found
in
65%
of
patients
with
GBS,
however,
disease
controls
were
not
studied
and
15%
of
healthy
controls
also
had
anti-
sulphatide
antibodies.6
In
contrast,
Ilyas
et
al
did
not
find
raised
anti-sulphatide
antibodies
in
GBS
by
TLC
and
ELISA,
when
titres
were
compared
with
normal
and
disease
controls.7
In
our
study
only
one
of
21
GBS
patients
had
raised
anti-sulphatide
antibody
titres.
Titres
were
highest
in
the
acute
phase
of
the
disease
and
returned
to
the
normal
range
within
three
weeks
suggesting
that
the
antibodies
were
related
to
the
disease.
Raised
titres
of
IgM,
IgG
or
IgA
anti-sulphatide
antibodies
may
be
an
infrequent
finding
in
GBS
patients
and
may
be
peculiar
to
patients
with
extensive
sensory
loss.
However,
a
larger
number
of
GBS
patients
will
have
to
be
tested
to
con-
firm
these
observations.
From
the
present
study
it
may
be
con-
cluded
that
raised
anti-sulphatide
antibody
titres
are
not
as
common
as
previously
sug-
gested
by
Pestronk
et
al,
who
found
raised
titres
in
18
of
64
(28%)
patients
with
sensory
±
motor
neuropathy.4
The
discrepancy
may
result
from
the
following
differences
in
our
assay
procedures:
a)
Pestronk
et
al
defined
high
titres
as
those
more
than
3
SD
above
the
mean
value
of
normal
controls.
We
found
that
using
this
method
a
substantial
number
of
patients
with
other
diseases
would
have
raised
titres.
We
considered
antibody
titres
to
be
raised
when
compared
with
normal
and
disease
controls.
b)
A
significant
number
of
patient
sera
have
relatively
high
binding
to
uncoated
control
wells.
In
our
study
values
in
uncoated
control
wells
were
subtracted
from
values
in
sulphatide-coated
wells
for
each
patient.
Using
this
method
only
antibody
binding
to
sulphatide
was
measured.
In
our
study
two
methods
of
calculating
antibody
titres
were
compared.
In
method
A
readings
were
taken
from
the
last
part
and
in
method
B
from
the
linear
part
of
the
OD
curve.
The
OD
curve
of
each
patient
has
a
different
shape,
which
explains
intra-individual
varia-
tions
of
results
from
method
A
or
B.
Although
both
methods
detect
highly
ele-
vated
antibody
titres,
we
prefer
method
A
for
routine
use,
as
values
at
higher
serum
dilu-
tions
suggest
higher
affinity
antibody
binding
and
may
be
more
accurate.
In
addition
values
from
method
B
are
more
difficult
to
compare
with
other
laboratories,
as
not
every
labora-
tory
may
use
the
same
positive
control.
The
role
of
anti-sulphatide
antibodies
in
1167
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van
den
Berg,
Lankamp,
de
Jager,
Notermans,
Sodaar,
Marmink,
de
Yong,
Bar,
Wokke
the
pathogenesis
of
neuropathy
is
still
unknown.
Sulphatide
is
a
common
glycolipid
found
in
spinal
cord
and
peripheral
nerve
tis-
sue,
and
is
highly
enriched
in
myelin.14
15
It
is
unlikely
that
the
antibodies
arise
as
a
result
of
tissue
breakdown,
as
raised
anti-sulphatide
antibodies
were
not
found
in
the
disease
con-
trols,
who
also
had
nerve
damage.
In
addi-
tion,
in
the
patient
with
GBS,
the
antibodies
were
present
in
high
titres
early
in
the
acute
phase
of
the
disease
before
significant
tissue
breakdown.
Several
sulphated
molecules
are
present
in
peripheral
nerve
tissue
and
cross-
reactivity
with
antibodies
binding
to
sul-
phatide
may
occur.
The
binding
site
and
the
fine
specificity
of
anti-sulphatide
antibodies
may
determine
the
particular
clinical
syn-
drome.
Thus
in
patients
who
have
predomi-
nantly
axonal
sensory
neuropathy,
binding
may
occur
to
sensory
axons
whereas
in
patients
with
demyelinating
neuropathy
(anti-
MAG
associated
or
GBS)
antibodies
may
be
directed
against
the
sulphatide
in
myelin.
However,
sensory
loss
as
the
common
feature
of
all
six
patients
with
raised
anti-sulphatide
antibodies
may
be
explained
by
antibody
binding
to
dorsal
root
ganglia.'6
Additional
motor
deficit
or
demyelination
may
result
from
binding
of
these
antibodies
to
cross-
reactive
sulphated
epitopes,
the
presence
of
associated
anti-MAG
activity
or
to
other
underlying
immune
abnormalities
that
may
occur
in
GBS.
In
five
of
the
six
patients
the
anti-sulphatide
antibodies
occurred
as
mono-
clonal
gammopathy
suggesting
a
primary
B-
cell
response.
In
GBS
the
presence
of
IgG
and
IgA
antibodies
suggests
T-cell
involve-
ment.
Testing
for
anti-sulphatide
antibodies
in
patients
with
peripheral
neuropathy
may
be
useful
to
study
possible
pathogenic
mecha-
nisms
in
a
subgroup
of
patients
with
sensory
neuropathy.
Treatment
strategies
in
these
patients
could
be
evaluated
by
measuring
antibody
titres.
Additional
testing
for
anti-
MAG
antibodies
is
necessary,
since
cross-
reactive
antibodies
occur
and
initial
symptoms
of
neuropathy
associated
with
anti-
MAG
antibodies
may
be
similar.'7
We
thank
Drs
N
Latov
and
SA
Sadiq
for
reading
the
manu-
script.
Professor
FGI
Jennekens
gave
useful
comments.
This
study
was
supported
by
the
Dutch
Organisation
for
Scientific
Research
and
the
Prinses
Beatrix
Fonds.
1
Ryberg
B.
Multiple
specificities
of
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in
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chronic
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1978;38:357-82.
2
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Vliet
HHDM,
Kappers-Klunne
MC,
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Hel
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J.
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in
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of
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idiopathic
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BrJHaematol
1987;67:103-8.
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Toda
G,
Ikeda
Y,
Kashiwagi
M,
Iwamori
M,
Oka
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plasma
membrane
glycosphingolipid
reac-
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with
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chronic
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as
sulphatide.
Hepawology
1990;12:664-70.
4
Pestronk
A,
Li
F,
Griffin
J,
Feldman
EL,
et
al.
Polyneuropathy
syndromes
associated
with
serum
anti-
bodies
to
sulphatide
and
myelin-associated
glycoprotein.
Neurology
1991;41:357-62.
5
Ilyas
AA,
Cook
SD,
Dalakas
MC,
Mithen
FA.
Anti-MAG
IgM
paraproteins
from
some
patients
with
polyneuropa-
thy
associated
with
IgM
paraproteinemia
also
react
with
sulphatide.
J
Neuroimmunol
1992;37:85-92.
6
Fredman
P,
Vedeler
CA,
Nyland
H,
Aarli
JA,
Svennerholm
L.
Antibodies
in
sera
from
patients
with
inflammatory
demyelinating
polyradiculoneuropathy
react
with
LM1
and
sulphatide
of
peripheral
nerve
myelin.
JNeurol
1991;238:75-9.
7
Ilyas.AA,
Mithen
FA,
Dalakas
MC,
et
al.
Antibodies
to
sulphated
glycolipids
in
Guillain-Barre
Syndrome.
JNeurol
Sci
1991;105:108-17.
8
Notermans
NC,
Wokke
JHJ,
Bar
PR,
Jennekens
FGI.
The
natural
course
in
chronic
idiopathic
-middle
and
old-
age
polyneuropathy
(CIAP).
J
Neurol
Sci
1990;98
(suppl):269.
9
Notermans
NC,
Wokke
HJ,
Jennekens
FGI.
Clinical
work-up
of
the
patient
with
a
polyneuropathy.
In:
JMBV
de
Jong,
ed.
Handbook
of
clinical
neurology,
vol
16.
Amsterdam:
Elsevier
Science
Publisher,
1991:253-70.
10
Van
den
Berg
LH,
Marrink
J,
De
Jager
AEJ,
De
Jong
HJ,
Van
Imhoff
GW,
Latov
N,
Sadiq
SA.
Anti-GMI
anti-
bodies
in
patients
with
Guillan-Barre
syndrome.
Y
Neurol
Neurosurg
Psychiatty
1992;55:8-1
1.
11
McGinnis
S,
Kohriyama
T,
Yu
RK,
Pesce
MA,
Latov
N.
Antibodies
to
sulphated
glucuronic
acid
containing
glycosphingolipids
in
neuropathy
associated
with
anti-MAG
antibodies
and
in
normal
subjects.
JNeuroimmunol
1988;17:119-26.
12
Van
den
Berg
LH,
Sadiq
SA,
Thomas
FP,
Latov
N.
Characterization
of
HNK-1
bearing
glycoproteins
in
human
peripheral
nerve
myelin.
J
Neurosci
Res
1990;25:295-9.
13
Hirabayashi
Y,
Suzuki
T,
Suzuki
Y,
et
al.
A
new
method
for
purification
of
anti-glycosphingolipid
antibody:
avian
anti-hematoside
(NeuGc)
antibody.
J
Biochem
1983;94:
327-30.
14
Svennerholm
L,
Fredman
P.
Antibody
detection
in
Guillain-Barre
Syndrome.
Ann
Neurol
1990;27(suppl):
S36-40.
15
Norton
WT,
Cammer
W.
Isolation
and
characterization
of
myelin.
In:
Morell
P,
ed.
Myelin,
2nd
edn.
New
York:
Plenum
Press,
1984:174-8.
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A,
Corbo
M,
Dodd
J,
et
al.
Anti-sulphatide
anti-
bodies
in
neuropathy.
J
Neuroimmunol
1991:supp
1:53.
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Latov
N,
Hays
AP,
Sherman
WH.
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neuropathy
and
anti-MAG
antibodies.
CRC
c?tical
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in
neuro-
biology,
Vol
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Inc
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1168
group.bmj.com on July 15, 2011 - Published by jnnp.bmj.comDownloaded from
doi: 10.1136/jnnp.56.11.1164
1993 56: 1164-1168J Neurol Neurosurg Psychiatry
L H van den Berg, C L Lankamp, A E de Jager, et al.
neuropathy.
Anti-sulphatide antibodies in peripheral
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... When we compared seroreactivities against glycosphingolipids between cluster and sporadic cases we noted a higher proportion of antibody-positive patients in the cluster [1, 3, 22, 38]. The clinical severity was worse in the cluster (F score C3), and cranial nerve damage was more frequent with the presence of anti-GQ1b/GalC antibodies suggesting that some patients shared overlapping features with the Miller Fisher variant of the disease [11, 12, 36, 37,[39][40][41][42]. The occurrence of high titer antibodies against sulfatide in two cluster patients was rather interesting, as cranial nerve damage with ataxia and sensory deficits were leading symptoms, and anti-sulfatide antibodies have been described to bind to cerebellar white and gray matter [13, 29, 30, 38] . ...
... The occurrence of high titer antibodies against sulfatide in two cluster patients was rather interesting, as cranial nerve damage with ataxia and sensory deficits were leading symptoms, and anti-sulfatide antibodies have been described to bind to cerebellar white and gray matter [13, 29, 30, 38] . Also, antisulfatide antibodies have been reported in patients with other peripheral neuropathies, however, the clinical relevance of those antibodies remains unclear in GBS [39][40][41][42][43][44][45][46]. In most cases, we obtained nerve conduction studies that were performed early after hospital admission. ...
Article
Full-text available
Few regional and seasonal Guillain–Barré syndrome (GBS) clusters have been reported so far. It is unknown whether patients suffering from sporadic GBS differ from GBS clusters with respect to clinical and paraclinical parameters, HLA association and antibody response to glycosphingolipids and Campylobacter jejuni (Cj). We examined 40 consecutive patients with GBS from the greater Munich area in Germany with 14 of those admitted within a period of 3 months in fall 2010 defining a cluster of GBS. Sequencing-based HLA typing of the HLA genes DRB1, DQB1, and DPB1 was performed, and ELISA for anti-glycosphingolipid antibodies was carried out. Clinical and paraclinical findings (Cj seroreactivity, cerebrospinal fluid parameters, and electrophysiology) were obtained and analyzed. GBS cluster patients were characterized by a more severe clinical phenotype with more patients requiring mechanical ventilation and higher frequencies of autoantibodies against sulfatide, GalC and certain ganglioside epitopes (54