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Anti-GD1a ganglioside antibodies in peripheral motor syndromes.

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ment, possibly indicating that these antibodies have
pathogenetic relevance. To determine the possible clinical relevance of these antibodies, we extensively investigated the presence and titers of anti-GD,, IgG and
IgM antibodies in the serum of patients with GRS and
those with different peripheral motor syndromes as
well as in several neurological and nonneurological
control subjects.
Anti-GD l a Ganglioside
Antibodies in IGripheral
Motor Syndromes
Marinella Carpo, MD,
Eduardo Nobile-Orazio, MD, PhD,
Nicoletta Meucci, MD, Massimo Gamba, MD,
Sergio Barbieri, M D , PhD, Silvia Allaria, and
Guglielmo Scarlato, M D
Materials and Methods
High titers of anti-GD,, antibodies have been found in
patients with Guillain-Bar& syndrome or motor neuropathy. To determine the possible diagnostic relevance of
these antibodies, we measured serum anti-GD,, IgG and
IgM antibodies by enzyme-linked immunosorbent assay
in 195 patients with different motor syndromes and in
335 control subjects. Moderately high antibody titers
(I/ 1,280-1/5,120) were occasionally found in patients
with chronic inflammatory demyelinatingpolyneuropathy
(5%), multifocal motor neuropathy (18%), lower motor
neuron disease (3.8%), or amyotrophic lateral sclerosis
(1.8%) and in immunological control subjects (1.2%),
while titers of 1/20,480 or higher were only found in 2
patients with Guillain-Barri! syndrome (IgG in both) and
2 with motor neuropathy and IgMX monoclonal gammopathy improving with immunotherapy. In both motor
neuropathy patients and the Guillain-Bar&syndrome patient who were retested during recovery, anti-GD,, titers
decreased concomitantly with clinical improvement. High
anti-GD,, antibody titers may be found in several motor syndromes but only markedly increased anti-GD,,
titers are strictly associated with potentially treatable dysimmune neuropathies.
Carpo M, Nobile-Orazio E, Meucci N, Camba M,
Barbieri S, Allaria S, Scarlato G. Anti-GD,,
ganglioside antibodies in peripheral motor
syndromes. Ann Neurol 1996;33:539-543
High titers of serum antibodies to the ganglioside GD,,
were demonstrated recently in some patients with Guillain-Bark syndrome (GBS) [l-51 and in a patient with
motor neuropathy (MN) associated with IgM monoclonal gammopathy [6], whereas lower antibody levels
were detected in patients with motor neuron disease
(MND) [7, 81. The anti-GD,, antibodies were mostly
IgG in patients with GBS and IgM in those with MN
or M N D and the titers, at least in GBS patients [l,
21, decreased concomitantly with clinical improveFrom the Institute of Clinical Neurology, Centro Din0 Ferrari,
Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
Received Jul 14, 1995, and in revised form Oct 2. Accepted for
publication Nov 9, 1995.
Address correspondence to Dr Nobile-Orazio, Institute of Clinical
Neurology, University of Milan, Via Francesco Sforza 35, 20122,
Milan, Italy.
W e studied sera from 73 patients with GBS [9], 20 with
chronic inflammatory demyelinating polyneuropathy (CIDP)
[lo], and 45 with a peripheral motor syndrome clinically
characterized by progressive limb weakness, reduced tendon
reflexes, no sign of bulbar or upper motor neuron impairment, and minimal or no sensory loss. In 11 of these patients, motor conduction studies revealed at least 40% conduction block (CB) [ 111 in two or more nerves, leading to
the diagnosis of multifocal motor neuropathy (MMN); 4 had
reduced motor conduction velocities (MCVs) (<8O% of the
lower normal limits) but no detectable CB and were considered to have M N [12], while 30 with normal or slightly
reduced MCVs were deemed to have lower motor neuron
disease (LMND). We also studied sera from 57 patients with
amyotrophic lateral sclerosis (ALS), 125 with other neuropathies, 81 with other neurological diseases, 82 with IgM or
IgG monoclonal gammopathy without neuropathy, 27 with
other immune diseases, and 20 healthy subjects. Patients’
sera were kept at -80°C until used.
Enzyme-Linked Immunosorbent Assay f i r Anti-GD,,
Anti-GD,, antibodies were measured by enzyme-linked immunosorbent assay (ELISA) as previously reported [13, 141
except that all steps were carried out at 4°C. Briefly, 1 pg of
purified CD,, (Sigma) was added in ethanol to each well in
microtitration plates (Costar) until evaporation. Wells were
saturated for 4 hours with 1% bovine serum albumin (BSA)
in phosphate-buffered saline (PBS) (saturating solution) and
incubated overnight with patients’ sera at the initial dilution
of 1 :320 in washing solution (saturating solution with 0.05%
Tween 20), and IgM and IgG reactivity was detected with
peroxidase-conjugated goat anti-human IgM or IgG (Cappel). Sera showing a difference of absorbance of more than
0.05 between GD,,- and BSA-coated wells were titrated by
twofold dilutions until negative (difference < 0.05). Sera with
high anti-GD,, titers were also tested by ELISA for reactivity
with G M , (Fidia, Italy), asialo-GM,, GDlb,and GM, (Sigma).
Immunostaining ajier High-Peerforyance Thin-Layer
Reactivity with GD,, and the other glycolipids was confirmed by immunostaining after high-performance thin-layer
chromatography (HPTLC) [ 141 of purified glycolipids (0.5
pg/lane, each). Sera were tested at 1: 100 dilution using peroxidase-conjugated rabbit antibodies to human IgG or IgM,
and in those with IgM M-protein, K or ;1 chain (Dakopatts,
Copyright 0 1996 by the American Neurological Association
1/327,680 -
IgM antibodies
IgG antibodies
1/81,920 -
1/20,480 -
Anti-GD,, IgM (open dots) and IgG (closed dots) antibody titers, by enzyme-linked immunosorbent assay, iii sera of patierits
with Guilhiri-Bnrre' syndrome (GBS), rbronir iirf(ctntmatovy demyelinating polyneuropathy (CIDP), multiforal motor neuropathy
(MMN), clinical4 pure motor neuropathy (MN), lower motor neuron disease (LMND), arnyotrophir lateral srlerosis (ALS), other
other neurologircll diseases (OND), serum M-protein without neuropathy (M-protein to PN), or other immuneuropathies (I"),
nological diseases (OID) and healthy nor?nal subjerts (NS). Moderateiy high antibody titers (r/l,28o-r/5,120) were found in
several patients with chronic motor syndromes while uery high antibody titers were only present in 2 pntients with GBS and 2
with MN. The upper normal limit for antibody titers is marked (n.v.). The numbers ofpatients examined in earh group are in
parentheses and those of the patients negative at the initial serum dilution of 1 :320 are in brackets.
Zmmunoafinity PurtJicrztion of Anti-GD,, Antibodies
In the 2 patients with MN and IgM gammopathy, anti-GD,,
antibodies were purified by affinity chromatography using a
GD,,-coated octyl-sepharose4B column ( I mg of GD,,/2 ml
of octyl-sepharose) [15]. Serum was applied to the column
for 1 hour. After extensive washing with PBS, antibodies
were eluted with 3 M NaSCN in I'BS and tested by ELISA
and overlay HPTLC for reactivity with glycolipids and by
agarose gel electrophoresis (AGE) to verify their correspondence with the M-protein.
Antibody Titers
Anti-GD,, antibody titers of 1/1,280 or more were
found by ELISA in I0 of the 530 patients tested (Fig)
including 2 with GBS (2.7%), 1 with CIDP (5%) and
IgGK monoclonal gammopathy, 2 with MMN (18%),
2 with M N (500/0) (both with IgMh M-protein), and
1 each with LMND (3.8%), ALS (1.80/0), and myas-
Annals of Neurology
Vol 39
No 4
April 1996
thenia gravis (1.2% of patients with other immune diseases). Most of these patients had moderately high antibody titers (11/5,120) whereas titers of 1/20,480 or
higher were only found in the 2 GBS patients (IgG in
both) and in the 2 with M N and IgM gammopathy.
One MN patient had a concomitant, though less
intense (1/20,480 vs 1/655,360) IgM reactivity by
ELISA with GM,, asialo-GMI, and GD,,,, while the
other also had high anti-GM2 (1/163,840) and antiGM, and -GDlb IgM titers (1/5,120). No reactivity
with other glycolipids was found by ELISA in the other
positive patients. Reactivity with GD,, and the other
glycolipids was confirmed in all patients by overlay
HPTLC. In both MN patients, IgM antibodies to
GD,, and the other glycolipids had the same light
chain of the M-protein, and when purified by affinity
Chromatography, migrated by AGE as a single band
comigrating with the M-protein and bound by ELISA
and overlay HPTLC to GD,, and cross reactive glycolipids.
CLinical Findings
Of the 2 patients with GBS and high anti-GD,, IgG
titers, 1 had a rapidly progressive, predominantly lower
limb weakness and was bedridden by the third day of
disease. She was treated with intravenous immunoglobulins (IVIg) (0.4 gm/kg/day X 5 days) and by 2
months could walk unassisted. Her anti-GD,, IgG titer
was I/20,480 on the third day of disease and normal
1 month later. The other GBS patient had rapidly progressive, severe weakness affecting extraocular, facial,
limb, and respiratory muscles and required assisted
ventilation for 12 days. MCVs were reduced in the
median (28 m/sec; compound motor action potential
[CMAP] amplitude, 1.3 mV) and peroneal (33m/sec,
2.5 mV) nerves. The patient improved after plasma
exchange but was still unable to walk at 6 months. The
anti-GD,, IgG titer was 1/20,480 on the tenth day of
disease, before plasma exchange, but was not subsequently measured.
Of the 2 MN patients with high anti-GDI, IgM
titers, 1 was a 66-year-old woman with an 8-month
history of progressive limb weakness. When first examined in July 1993, she had difficulty walking and could
not handle small objects. She had bilateral, slight wasting and weakness of the intrinsic hand muscles and
severe, predominantly distal weakness without
hypotrophy in the lower limbs. Tendon reflexes were
ubiquitary absent. Sensation was normal. Laboratory
tests disclosed an IgMh monoclonal gammopathy of
undetermined significance (MGUS) (IgM, 800 mg/dl)
and cryoglobulinemia. Cerebrospinal fluid (CSF) proteins were 60 mg/dl and cells, l/pL. MCV and CMAP
amplitudes were reduced in the median (40 mlsec, 2.3
mV), ulnar (35 m/sec, 4.1 mV), and peroneal (32 m/
sec, 1.3 mV) nerves. Sensory studies revealed normal
findings in sural nerve but reduced sensory action potential (SAP) amplitudes with normal latencies in the
median and ulnar nerves. Pathological studies on sural
nerve biopsy specimens showed segmental demyelination and axonal degeneration. The patient did not
respond to IVIg (0.4 gm/kg/day X 5 days) and oral
cyclophosphamide (2 mg/kg/day X 6 months) and by
February 1994 could stand only with assistance. At
that time MCVs were further reduced in the median
(35.7 mlsec) and ulnar (29.5 mlsec) nerves. Sensation
was normal but SAPS were ubiquitary absent. Oral
prednisone (1 mg/kg/day) was added to cyclophosphamide, resulting in a slight but progressive improvement
so that after 6 months she could stand alone and walk
with a cane. Three months later she died of congestive
heart failure. Anti-GD,, titers were stable during IVIg
and cyclophosphamide treatment and decreased by
fourfold during steroid therapy.
The other MN patient with high anti-GD,, IgM
titers was a 63-year-old woman with a 6-month history
of progressive, asymmetrical limb weakness. When admitted in October 1993, she was unable to walk unassisted and had no use of the upper limbs. She had
asymmetrical, predominantly distal, severe limb weakness with slight hypotrophy of the intrinsic hand muscles. Tendon reflexes were ubiquitary absent except for
reduced knee jerks. Sensation was normal. Laboratory
tests revealed an IgMk MGUS (IgM, 900 mg/dl). CSF
proteins were 78 mg/dl and cells, 3/c~L.CMAP amplitudes and MCVs were reduced in the median (1 mV,
26.5 m/sec), ulnar (1.6 mV, 27.2 m/sec), and peroneal
(40 pV, proximal CMAP not evoked) nerves, while
sensory studies revealed normal findings in the median,
ulnar, and sural nerves. Sural nerve biopsy specimens
showed axonal degeneration and segmental demyelination but no deposits of IglM by direct immunofluorescence. The patient was treated with IVIg, with a
rapid improvement in limb strength, followed 2 weeks
later by a rapid deterioration. This deterioration was
not halted by repeated IVIg infusions with oral prednisone and by five plasma exchanges (2 liters each) on
alternate days; the patient became almost completely
paralyzed. She was then treated with 2-day IVIg infusions every I0 to 14 days and oral cyclophosphamide
(2+1 nig/kg/day). The patient gradually improved. At
the time of writing she walked without support and
used her arms to dress and feed but still required IVIg
infusions every 1 to 2 months. Anti-GD,,, titers decreased by fourfold during IVIg and cyclophosphamide
In this study, high anti-GD,, antibody titers were almost invariably found in patients with prominent motor impairment, but only titers of 1/20,480 or higher
were always associated with a potentially treatable dysimmune neuropathy including GBS (in the case of IgG
antibodies) and MN associated with IgM MGUS (IgM
antibodies). High titers of anti-GD,,*IgG antibodies
were recently associated with severe forms of GBS characterized by prominent axonal degeneration and poor
prognosis [ l , 21. This clinical pattern was present in 1
of our GBS patients whose electrophysiological findings were consistent with a dernyelinating process,
while the other recovered to independent ambulation
within 2 months, indicating that, similarly to what has
been reported for anti-GMI antibodies (reviewed in
[ 1GI), the association of anti-GD,, antibodies with severe forms of GBS may not be invariably seen [ 5 ] . A
selectively high anti-GD,, IgM reactivity previously was
demonstrated in a patient with a demyelinating MN
Brief Communication: Carpo et al: Anti-GD,, Antibodies and Neuropathy
associated with ISM monoclonal gammopathy whose
condition stabilized during immunosuppressive therapy
[6].Both our patients with high anti-GD,, IgM titers
also had a clinically pure motor demyelinating neuropathy associated with IgM MGUS, even if one had absent SAPS in all sensory nerves. This relatively honiogeneous presentation and the decrease of antibody levels
in both our patients concomitant with clinical improvement suggest that the association of anti-GD,,
IgM M-proteins with MN, though infrequent, may
not be coincidental.
If the association of moderately high anti-GD,, levels
with several forms of predominantly motor neuropathies and with ALS and other immune disorders [7]
makes it unlikely that these antibody levels have a primary pathogenetic role, the constant association of
markedly increased titers with dysimmune neuropathies [ l , 2, 6 ) and their decrease during clinical improvement suggest that at least at these levels, they may
have pathogenetic relevance. Furthermore, in our series, both GBS patients had high IgG antibodies specifically reacting with GD,,l,while those with MN had
IgM antibodies that also bound to other glycolipids,
including GM,, GD,b,and either a d o - G M , or GML,
possibly indicating that the different isotypes or specificities of these antibodies correlate with different diseases. However, since IgM reactivity with any of these
glycolipids, but mostly G M , , also has been associated
with motor neuropathies (reviewed in [17]), it is not
possible to determine which of these glycolipids, if any,
was bound by patients’ M-proteins in vivo, and if so,
which cause the neuropathy. Both G M i and GD,,,are
more concentrated in the motor than in the sensory
nerves and in the axon than in myelin [18, 131. This
distribution could theoretically explain the predominant motor impairment seen in patients with high antiG M , or anti-GD,, antibodies and possibly the prominent axonal impairment sometimes observed in GBS
patients with anti-GD,, [ I , 2, 51 or anti-GM, IgG [ 5 ,
20, 211. However, whether these findings are related
to the tissue distribution of the antigen or as recently
shown for anti-GM, antibodies [22], to a different
antineural effect of the antibody depending on the
presence or activation of complement is not known.
Further studies on the binding capabilities in vivo of
these antibodies and on their mechanism of action in
vitro will probably help clarify their pathogenetic role.
Ospedale Sail Gerardo, Monza. for providing sera and clinical data
for some GBS patients.
Presented in part at the fifth meeting of the European Neurological
Society, Munich, Germany, June 17-21, 1395.
1. Yuki N, Yoshino H , Sat0 S, et al. Severe acute axonal form of
Guillain-BarrC syndrome associated with anti-GD 1a antibodies.
Muscle Nerve 1992;l
1 Yuki N, Yaniada M ,
This work was made possible by the financial support of Associazione Amici Cenrro Dino Ferrari and by grants from Telethon, Italy
(grant 486), Associazione ltaliana Sclerosi Multipla, Italian National
Research Council. and IRCCS Ospedale Maggiore Policlinico. Milan, Iraly.
We would like to thank Dr Ivl. Moggio from our institute for
morphological srudies o n sural nerve specimen<. and Dr A. Fasanaro
from Ospedalr Cardarelli. Naples, and Dr G . Cavalctti from
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April 1996
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ataxia, areflexia, and widespread sensory loss with poor
recovery [I]. There is no association with neoplastic or
immunological disease. Since the original description
[l],several similar patients have been reported [2-51;
pathological evaluation, however, has been limited to
sural nerve biopsy specimens. W e describe a patient
with acute sensory neuronopathy with minor signs of
autonomic dysfunction a n d include, for the first time,
detailed autopsy findings.
Patient History
T Cell-mediated
Ganglionitis Associated
with Acute Sensory
Johann Andreas Hainfellner, MD,*
Wolfgang Kristoferitsch, MD,? Hans Lassmann, MD,*
Hanno Bernheimer, MD," Andrea Neisser, MSc,*
Marcus Drlicek, MD,Q Franz Beer, MD,$
and Herbert Budka, M D "
A 67-year-old man presented with acute painful sensory
loss, areflexia, ataxia, urinary retention, and severe constipation and became unable to walk within 2 weeks. He
died suddenly 5 weeks after the onset of symptoms. Autopsy revealed widespread inflammation of sensory and
autonomic ganglia with immunocytochemicalevidence of
a CD8' T cell-mediated cytotoxic attack against ganglion
neurons. This observation suggests a novel pathogenetic
mechanism of immune-mediated human ganglion cell
damage comparable to mechanisms operating in polymyositis.
Hainfellner JA, Kristoferitsch W, Lassmann H,
Bernheimer H,Neisser A, Drlicek M, Beer F,
Budka H. T cell-mediated ganglionitis
associated with acute sensory neuronopathy.
Ann Neurol 1996;39:543-547
T h e acute sensory neuronopathy syndrome is characterized by a monophasic course with rapidly evolving
From the *Institute of Neurology, University of Vienna: the Hospital Sozialmedizinisches Zentrum Ost, ?Neurological Department
and $Institute of Pathology; and the SHospital Pulmologisches
Zentrum Baumgartner Hohe, Institute of Pathology, Vienna,
Received Aug 17, 1995, and in revised form Nov 8. Accepted for
publication Nov 14, 1995.
Address correspondence to Dr Budka, Institute of Neurology,
AKH, Wahringer Giirrel 18-20, POB 48, A-1097 Wien, Austria.
A 67-year-old man was healthy until 2 weeks before admission. He noted tingling paresthesia in both hands, which
extended to both arms within 3 days, and burning pain on
the back, the costal arches, and the upper belly. Four days
before admission, gait became unsteady and deteriorated rapidly. O n admission, the patient came in a wheelchair and
was unable to walk without support. There was no history
of antecedent infection or of exposure to toxic substances
or antibiotics. The patient was alert and orienred. Ocular
movements, speech, function of other cranial nerves, and
muscle bulk and strength were normal. The triceps jerks were
trace positive; all other deep tendon reflexes were absent, and
the plantar responses were flexor. In the lower extremities,
vibratory sensation was absent; position sense of joints was
lost in the distal parts; pain and temperature senses were
reduced, with a level at T-8 on the right and T-12 on the
left. Hyperpathia was present in the distal rwo thirds of the
lower legs. In the upper limbs, light touch sense was slightly
reduced but the other sensory modalities were normal. Severe
truncal and limb sensory ataxia prevented the patient from
standing and walking unaided. Electroneurography was performed in four sessions within 2 weeks after admission. Motor nerve conduction velocity and compound muscle action
potential amplitudes of the right median and peroneal nerves
and sensory conduction velocity (SCV) of the right median
nerve were normal; SCV of the left sural nerve was slightly
slowed (37 m/sec; normal range: >37.6 m/sec). Electromyography of the right anterior tibia1 muscle indicated a slight
neurogenic lesion (prolonged duration of muscle action potentials and more than 20% polyphasic potentials). Blood
sedimentation rate was 13 mm in the first and 19 mm in
the second hour. In serum, the total protein concentration
was 59 mgidl and IgG, 7.1 gidliter (normal range: 8-16
g d l i t e r ) . Serological screening results for neurotropic viruses, Toxoplasrna gondii, Treponema pallidum, Borrelia
burgdop-ferz, and human immunodeficiency virus (HIV) type
1 in blood and cerebrospinal fluid (CSF) were negative. Antibodies against gangliosides GM,, GD,,, GDlh, GT,b, GM2,
and GM4 as well as against asialo-GM, were examined by
thin-layer chromatography and immunostaining [6]. At 1 :
200 serum dilution, IgG bound strongly to a d o - G M , ,
GM,, and GM2 and weakly to GD1,, GDIb,and GT,,, (normal controls are negative for antiganglioside antibodies ar 1 :
50 serum dilution). Antinuclear antibodies (anti-Ro, -La,
-U1-RNP, -Sm, -Scl-70, and -Jo-I), investigated by Ouchterlony double diffusion (Immuno Concepts, Sacramento,
CA) and enzyme-linked immunosorbent assay (Medizintechnik, Freiburg, Germany), as well as antineuronal antibodies
of the anti-Hu, -Ri, and -Yo type, tested by immunofluores-
Copyright 0 1996 by the American Neurological Association
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