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Cerebellar Ataxia With Anti–Glutamic Acid Decarboxylase Antibodies
Study of 14 Patients
Jérôme Honnorat, MD, PhD;
Albert Saiz, MD;
Bruno Giometto, MD;
Angela Vincent, FRCPath;
Luis Brieva, MD;
Clara de Andres, MD;
José Maestre, MD;
Nicole Fabien, MD;
Alain Vighetto, MD;
Roser Casamitjana, MD;
Charles Thivolet, MD;
Bruno Tavolato, MD;
Jean Christophe Antoine, MD;
Paul Trouillas, MD;
Francesc Graus, MD
Arch Neurol. 2001;58:225-230.
ABSTRACT
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Background Antibodies to glutamic acid decarboxylase (GAD-Ab) are described in
patients with insulin-dependent (type 1) diabetes mellitus (IDDM), in stiff-man
syndrome, and, recently, in a few patients with cerebellar ataxia.
Objectives To show a link between GAD-Ab and some patients with cerebellar ataxia
and to clarify their clinical and immunologic profiles.
Methods Serum samples were selected from 9000 samples of 4 laboratories. The
selection criterion was an immunohistochemical pattern compatible with GAD-Ab
that was confirmed by radioimmunoassay. We identified 22 patients with stiff-man
syndrome and 14 with cerebellar ataxia and GAD-Ab.
Results Thirteen of the 14 patients with cerebellar ataxia and GAD-Ab were women,
and 11 had late-onset IDDM. Patients did not have clinical or radiologic evidence
of brainstem involvement. Ten patients had oligoclonal IgG bands in the cerebrospinal
fluid, and intrathecal GAD-Ab synthesis was observed in 5 of the 6 patients
studied. The level of GAD-Ab of these patients was similar to those with stiff-man
syndrome and significantly higher than those with IDDM or with polyendocrine
autoimmunity (P<.001). However, the GAD-Ab levels
of 6 of the 9 patients with polyendocrine autoimmunity overlapped with those
of patients with cerebellar ataxia.
Conclusions These results suggest a link between high level of GAD-Ab and some cases
of cerebellar ataxia, particularly women with IDDM. If high serum levels of
GAD-Ab are detected, the cerebrospinal fluid should be evaluated for the presence
of oligoclonal IgG bands and intrathecal synthesis of GAD-Ab to further prove
an autoimmune origin of the syndrome.
INTRODUCTION
GLUTAMIC acid decarboxylase (GAD) is a major enzyme of the nervous system
that catalyzes the conversion of glutamate to  -aminobutyric acid (GABA).
This enzyme, also expressed by pancreatic beta cells, has been identified
as a dominant and essential autoantigen in the development of insulin-dependent
(type 1) diabetes mellitus (IDDM).1 Anti-GAD
autoantibodies (GAD-Ab) are present in up to 80% of patients with newly diagnosed
IDDM and can be detected many years before the clinical onset of the disease.2 High levels of GAD-Ab are found in the serum and cerebrospinal
fluid (CSF) of at least 60% of patients with the stiff-man syndrome, a rare
disorder of the central nervous system characterized by progressive muscle
rigidity with superimposed painful spasms.3, 4
Patients with stiff-man syndrome who have GAD-Ab usually also have IDDM and
other organ-specific autoimmune manifestations, suggesting that the stiff-man
syndrome may have an autoimmune-mediated pathogenesis.5
The GAD-Ab of patients with stiff-man syndrome are in higher titer and have
a different epitope specificity than those of patients with IDDM, suggesting
that the 2 diseases may have different autoimmune mechanisms.6, 7
Recent studies show that high levels of GAD-Ab may also be observed
in a few patients with cerebellar ataxia, supporting an autoimmune pathogenesis
of the cerebellar syndrome.8, 9, 10, 11, 12, 13, 14
To confirm this clinical-immunologic association, we describe a series of
14 patients with idiopathic cerebellar ataxia and high titers of GAD-Ab.
PATIENTS AND METHODS
PATIENTS AND SERUM SAMPLES
Serum samples were selected from those sent to 4 European laboratories
(Barcelona, Spain; Lyon and Saint-Etienne, France; and Padua, Italy) to test
for the presence of antineuronal autoantibodies associated with paraneoplastic
neurologic syndromes. The selection criterion was an immunohistochemical pattern
compatible with GAD-Ab. The presence of GAD-Ab was confirmed by radioimmunoassay
(RIA) in 2 centers. Thirty-six serum samples from more than 9000 showed an
immunohistochemical pattern compatible with GAD-Ab; 22 of them were from patients
with typical stiff-man syndrome and the other 14 had ataxia as the predominant
neurologic symptom. None of the selected serum samples had anti-Hu, anti-Yo,
anti-CV2, anti-Tr, or anti-Ri antibodies The clinical features of these 14
patients were obtained by personal clinical interview and neurologic examination,
to establish the presence of a personal or familial history of autoimmune
disorders and evolution of ataxia. Samples of CSF were obtained from all patients
for standard examination and the presence of IgG oligoclonal bands. In 6 patients,
paired serum-CSF samples were available to analyze a possible intrathecal
synthesis of GAD-Ab.
To standardize the immunologic data, serum and, when available, CSF
samples of the 14 patients were reevaluated by the techniques described below.
The samples detected by immunohistochemical analysis were sent to the different
laboratories with positive and negative controls (20 with idiopathic late-onset
cerebellar ataxia and no anti-GAD reactivity by immunohistochemical analysis;
9 with polyendocrine autoimmunity [IDDM and thyroiditis] without neurologic
symptoms and selected for presenting high GAD-Ab levels by RIA; 91 healthy
subjects; 10 patients with stiff-man syndrome; and 49 with recent diagnosis
of IDDM) and tested without awareness of the clinical diagnosis.
IMMUNOHISTOCHEMICAL ANALYSIS
Immunohistochemical analysis was performed on frozen sections of paraformaldehyde-fixed
rat cerebellum by means of an avidin-biotin immunoperoxidase (Barcelona's
laboratory) and indirect immunofluorescence technique (Lyon's laboratory)
as previously described.10, 12
Intrathecal synthesis of GAD-Ab was determined by means of the reciprocals
of end-point titers determined by immunohistochemical analysis of paired serum-CSF
samples and applying the Schüller formula as previously described.12 A ratio greater than 2 was considered positive for
intrathecal synthesis.
IMMUNOBLOT
Immunoblots were done in Barcelona with a technique previously described.12 Briefly, human GAD65 recombinant protein (CIS Biointernational,
Gif-sur-Yvette, France) (0.16 µg per lane) was electrophoretically separated
in a 10% sodium dodecyl sulfate–polyacrylamide gel and transferred to
nitrocellulose.15 Strips were sequentially
incubated with the patient's serum or GAD-6 monoclonal antibody (Hybridoma
Bank, Iowa City, Iowa), immunoreacted with an avidin-biotin technique, and
developed with diaminobenzidine tetrahydrochloride (Sigma-Aldrich Corp, St
Louis, Mo).
RADIOIMMUNOASSAY
To confirm the anti-GAD specificity of the serum samples that were positive
on immunohistochemical analysis, RIAs were performed with GAD labeled with
iodine 125 (125I), obtained from 1 of 2 sources (CIS Biointernational
or RSR Ltd [Cardiff, Wales]). In the Barcelona laboratory 125I-GAD
was used according to the manufacturer's instructions12, 16;
in the Oxford, England, laboratory slight modifications were made as previously
described.17
DETECTION OF OTHER AUTOANTIBODIES
Serum samples from the 14 patients with ataxia who had GAD-Ab and the
20 patients with idiopathic late-onset cerebellar ataxia and no anti-GAD reactivity
by immunohistochemical analysis were tested in the Lyon laboratory for the
presence of other organ-specific autoantibodies. Antinuclear, antiendomysium,
antiadrenal, antipituitary, and antistomach autoantibodies were detected by
an indirect immunofluorescence technique as previously described.18 Antithyroperoxidase, antithyroglobulin, antigliadin,
and anti–parietal cell autoantibodies were detected by enzyme-linked
immunosorbent assay commercial kits according to the instructions of the manufacturers
(Pharmacia Upjohn Diagnostics, Uppsala, Sweden, and Sigma Chemical Co, Paris,
France). The IA2 antibodies were detected by radioligand assay.19
RESULTS
CLINICAL FEATURES
The main clinical features of the 14 patients with GAD-Ab and cerebellar
ataxia are summarized in Table 1
and Table 2 and include 4 patients
(patients 1-4) who were previously described.10, 11, 12
Thirteen of them were women, with a median age of 51 years (range, 20-74 years)
at the onset of the cerebellar syndrome. Six patients had a family history
of autoimmune diseases such as IDDM or thyroiditis, but none had a family
history of cerebellar ataxia. Ten of 14 patients had IDDM. In all cases, these
patients had a late-onset IDDM that started at a median age of 47 years (range,
28-66 years). The diagnosis of IDDM antedated the onset of the cerebellar
syndrome in 7 patients (median, 8 years; range, 2-12 years). Other autoimmune
disorders were thyroiditis (Hashimoto or Graves disease) (8 patients), pernicious
anemia (2 patients), myasthenia gravis (1 patient), and psoriasis (1 patient).
An asymptomatic celiac disease was diagnosed by duodenal biopsy in 1 patient
after antigliadin autoantibodies were detected by a systematic test. Two patients
presented with thymoma 3 years before and 2 years after the diagnosis of the
cerebellar ataxia.
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Table 1. Autoimmune Features in Patients With Cerebellar Ataxia and
GAD-Ab*
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Table 2. Neurologic and CSF Characteristics of Patients With Cerebellar
Ataxia and GAD-Ab*
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The cerebellar ataxia that developed in these 14 patients was similar
(Table 2). A subacute onset was
observed in only 1 case, whereas symptoms progressed slowly, suggesting a
degenerative disease, in 13 patients. The main cerebellar sign, which was
present in all of the patients, was gait ataxia that was moderate or severe
in 10. Limb ataxia was also observed in 12 patients, but was rated as mild
in 7. The cerebellar symptoms prevented a completely independent way of life
(Rankin score, >2) in 10 patients. Nystagmus was observed in 12 patients and
dysarthria in 8. Associated neurologic symptoms were leg rigidity suggesting
a focal stiff-man syndrome (2 patients), peripheral neuropathy (1 patient),
and myasthenia gravis (1 patient). The CSF examination gave normal results
in only 4 patients. For the 10 other patients, CSF analysis showed a normal
protein level, but isoelectric focusing and immunoblot of IgG detected oligoclonal
IgG bands not present in the serum. Three patients had a high IgG index. Only
1 patient had an abnormal cell count (7 lymphocytes). Magnetic resonance images
of the brain were normal in 7 patients and showed pure cerebellar atrophy
in the others. One patient had an associated Arnold-Chiari type I malformation
(patient 4), but none showed brainstem atrophy.
IMMUNOLOGIC STUDIES
The RIA confirmed anti-GAD reactivity observed by immunohistochemical
analysis in all 14 serum samples by the 2 laboratories with complete agreement.
A positive intrathecal synthesis of GAD-Ab was observed in 5 of the 6 patients
who had paired serum-CSF samples available (median, 11.5; range, 2.9-16.4).
All 14 serum samples of patients with cerebellar ataxia had a high level
of GAD-Ab by RIA (Figure 1). The
mean (± SD) level of GAD-Ab in these patients (37 300 ±
30 460 U/mL) was similar to the level in those with stiff-man syndrome
(21 750 ± 19 280 U/mL) and significantly higher than the
level in those with a recent diagnosis of IDDM (48 ± 112 U/mL) or with
polyendocrine autoimmunity without neurologic disease (5828 ± 9355
U/mL) (P<.001). However, in 6 of the 9 patients
with polyendocrine autoimmunity, serum GAD-Ab levels overlapped with those
of patients with cerebellar ataxia and GAD-Ab (Figure 1). None of the control patients with idiopathic late-onset
cerebellar ataxia without GAD reactivity by immunohistochemical analysis or
the normal subjects had GAD-Ab by RIA.
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Figure 1. Levels of antibodies to glutamic
acid decarboxylase (GAD), by radioimmunoassay (Barcelona, Spain), expressed
in arbitrary units. 1 indicates controls (n = 91); 2, patients with insulin-dependent
(type 1) diabetes mellitus (n = 49); 3, patients with polyendocrine autoimmunity
(n = 9); and 4, patients with cerebellar ataxia with GAD antibodies (n = 14).
The horizontal line represents the median value of the normal subjects plus
3 SDs.
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The 14 serum samples displayed a band in immunoblots of GAD65 recombinant
protein with the same electrophoretic mobility as that recognized by GAD-6
monoclonal antibody (Figure 2).
A similar band was also observed with 7 of the 9 serum samples from patients
with polyendocrine autoimmunity without neurologic disease (data not shown).
Other organ-specific autoantibodies were detected in 11 of the 14 patients
with cerebellar ataxia and GAD-Ab (Table
1) and only in 2 of the 20 with idiopathic late-onset cerebellar
ataxia without GAD-Ab (P<.01). The 2 patients
showed antithyroperoxidase antibodies, but none of them had antigliadin or
antiendomysium antibodies.
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Figure 2. Immunoblots of GAD65 recombinant
protein probed with the serum of patients with cerebellar ataxia and antibodies
to glutamic acid decarboxylase (GAD-Ab) (lanes 2-15) and cerebellar ataxia
without GAD-Ab by immunohistochemical analysis (lanes 16-17). The immunoreactive
bands have the same electrophoretic mobility as that recognized by GAD-6,
a monoclonal antibody directed against GAD65 (lane 1). Serum dilutions of
the positive control and patients with cerebellar ataxia and GAD-Ab were adjusted
to the GAD-Ab level by radioimmunoassay. Lanes 2 to 4, 1:20 000; lanes
5 to 6, 1:10 000; lanes 7 to 17, 1:5000.
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COMMENT
This study describes a series of patients with cerebellar ataxia and
high titers of GAD-Ab. It is important to recognize this subgroup of patients
because they may respond to immunotherapies. Previous case reports of cerebellar
ataxia and high titers of GAD-Ab did not establish a clear relationship between
the presence of GAD-Ab and the cerebellar ataxia.8, 9, 10, 11, 12, 13, 14
The presence in most of these patients of oligoclonal bands in the CSF, GAD-Ab
intrathecal synthesis, and late-onset IDDM and other organ-specific autoimmune
disorders clearly distinguishes them from those with other nonfamilial late-onset
cerebellar ataxia.
All but 1 patient presented with an insidious cerebellar ataxia without
brainstem involvement that would fit in the first group of Harding's classification
on idiopathic late-onset cerebellar ataxia20
and that corresponds to the old Marie-Foix-Alajouanine type of cerebellar
degeneration.21 We did not observe clinical
or radiologic evidence of brainstem involvement, suggesting in our patients
an olivopontocerebellar atrophy. Two patients had rigidity of one leg not
explained by corticospinal tract dysfunction. These patients probably had
a focal form of stiff-man syndrome.22 The co-occurrence
of stiff-man syndrome and cerebellar ataxia with high titer of GAD-Ab was
also described in 2 other patients in the literature.11, 23
These facts suggest an overlap between the 2 neurologic symptoms and further
emphasize the association of GAD-Ab with both cerebellar ataxia and stiff-man
syndrome and suggest common pathologic mechanisms.
The clinical and serologic data of our 14 patients favor an immune system
dysregulation. All but 1 patient were women, and many had other organ-specific,
mostly endocrine, autoimmune manifestations. Indeed, all but 2 patients had
evidence of other autoimmune disorders. Late-onset IDDM was observed in 71%
of patients, thyroiditis in 57%, and a family history of autoimmune disorders
in 43%. Furthermore, 2 patients developed a thymoma that is commonly associated
with autoimmune neurologic or hematologic disorders. This clinical and immunologic
profile is similar to that observed in stiff-man syndrome with GAD-Ab, in
which 30% have IDDM.5 Finally, other organ-specific
autoantibodies were observed in 79% of our patients, compared with only 10%
of our control patients with cerebellar ataxia but without GAD-Ab.
Two of our patients with GAD-Ab also had serum IgA antigliadin antibodies.
These antibodies have recently been described in patients with late-onset
cerebellar ataxia, gluten sensitivity, and appropriate HLA genotype for celiac
disease.24 However, patients with gluten ataxia
differ from those with GAD-Ab by the preponderance of males, high frequency
of peripheral neuropathy, and low prevalence of nystagmus.24, 25
Therefore, the presence of antigliadin antibodies in 2 of our patients probably
reflects the coincidence with other autoimmune disorder without direct relation
to the cerebellar ataxia.
Although there is evidence of immune dysregulation in our group of patients,
the pathogenic role of autoimmunity and GAD-Ab in the cerebellar ataxia remains
unclear. The GAD-Ab could merely reflect the presence of IDDM and polyendocrine
autoimmunity observed in our patients. In fact, our selected control patients
with polyendocrine autoimmunity without neurologic disease demonstrate that
a high titer of GAD-Ab in the serum does not necessarily indicate an association
with a given neurologic disorder. However, this possibility would not apply
to the 4 patients who did not have IDDM, and our patients showed elevated
intrathecal synthesis of GAD-Ab and positive oligoclonal IgG bands in the
CSF. Both features indicate an active immune process in the nervous system
that should not be expected if the cerebellar ataxia had a degenerative cause.
Recent work suggested that the GAD-Ab from patients with stiff-man syndrome
could be pathogenic because, unlike the GAD-Ab from patients with IDDM, they
can reduce GAD enzyme activity and GABA synthesis.26
In 1 case of cerebellar ataxia, the GAD-Ab were able to cause a selective
suppression of GABA-ergic transmission in in vitro experiments with isolated
rat cerebellar slices.14 These studies, however,
do not explain how GAD-Ab can access the intracytoplasmic antigen and why
their actions are so selective compared with the widespread distribution of
GAD in the nervous system. An alternative explanation could be that the high
anti-GAD titers reflect only the presence of a more complex immune reaction
against the nervous system that could implicate a cell-mediated immune response
directed against GAD or other cerebellar antigens. Even if GAD is not the
key antigen, the immunologic profile of these patients and their predisposition
to develop organ-specific autoimmune manifestations, coupled with the presence
of oligoclonal IgG bands in the CSF, suggests an immune-mediated disorder
as the most probable pathogenesis of the cerebellar dysfunction.
In conclusion, our findings support a link between GAD autoimmunity
and some cases of idiopathic cerebellar ataxia. We suggest that testing for
GAD-Ab may be indicated in patients with cerebellar ataxia, particularly women
with late-onset IDDM or other organ-specific autoimmune diseases and absence
of brainstem involvement. If high levels of GAD-Ab are detected in the serum,
the CSF should be examined for oligoclonal IgG bands and intrathecal synthesis
of GAD-Ab. If CSF studies are positive, immune-mediated damage of the cerebellum
linked to GAD autoimmunity is highly probable and immunotherapy could be warranted.
AUTHOR INFORMATION
Accepted for publication October 2, 2000.
This study was supported in part by grant SGR 9500027, Generalitat de
Catalunya, Barcelona, Spain; Institut National de la Santé et de la
Récherche Médicale, Paris, France; La Fondation de France, Paris;
La Ligue contre le Cancer du Rhône, Lyon, France; l'Association pour
la Recherche contre le Cancer, Paris; and grant 756/01/97, Regione Veneto,
Venice, Italy.
We thank Mercé Bonastre and Michelle Aguera for their excellent
technical assistance and Isabelle Serre, MD, Caroline Tilikete, MD, and Bernard
Carlander, MD, who provided some clinical data.
From the Ataxia Research Center, Neurology B (Drs Honnorat and Trouillas)
and Department of Neurology C (Dr Vighetto), Hôpital Neurologique, Lyon,
France; Institut d'Investigació Biomèdica August Pi i Sunyer
(Drs Saiz, Casamitjana, and Graus) and Department of Neurology and Laboratorio
de Hormonal (Dr Casamitjana), Hospital Clinic, University of Barcelona, Barcelona,
Spain; Department of Neurology and Psychiatry (Second Neurologic Clinic),
University of Padua, Padua, Italy (Drs Giometto and Tavolato); Neurosciences
Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, England
(Dr Vincent); Department of Neurology, Hospital General Universitari, Vall
d'Hebrón, Barcelona (Dr Brieva); Department of Neurology, Hospital
Gregorio Marañón, Madrid, Spain (Dr de Andres); Department of
Neurology, Hospital Virgen de las Nieves, Granada, Spain (Dr Maestre); Department
of Immunology, Centre Hospitalier Lyon-Sud, Pierre-Benite, France (Dr Fabien);
Institut National de la Santé et de la Récherche Médicale
U 449, Faculté de Médecine Laennec, Lyon (Dr Thivolet); and
Department of Neurology, Hôpital Bellevue, St Etienne, France (Dr Antoine).
Corresponding author and reprints: Francesc Graus, MD, Service of
Neurology, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain
(e-mail: graus{at}medicina.ub.es).
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