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Clinical Neurology and Neurosurgery xxx (2012) xxxxxx

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Clinical Neurology and Neurosurgery

journal homepage: www.elsevier.com/locate/clineuro

Case report

Miller Fisher syndrome with positivity of anti-GAD antibodies

Vladimiro Pietrini a, , Giovanni Pavesi a , Francesca Andreetta b
a
Department of Neurosciences, Neurology Unit, University of Parma, Parma, Italy
b
Myopathology and Immunology Unit, Neurological Institute Foundation C Besta, Milan, Italy

a r t i c l e i n f o

Article history:
Received 27 June 2012
Received in revised form 18 October 2012
Accepted 16 November 2012
Available online xxx

Keywords:
Miller Fisher syndrome
Anti-GAD antibodies
Anti-GQ1b antibodies

1. Introduction neurotropic viruses and absence of oligoclonal bands. The stool

Miller Fisher syndrome (MFS) is a variant of Guillain Barr
syndrome (GBS) characterized by ophthalmoplegia, ataxia and are-
exia [1]. IgG antibodies against GQ1b are present in more than 90%
of acute MFS patients [2,3]. We report a case with typical clinical
and electrophysiological features of MFS with no anti-GQ1b anti-
bodies in the blood serum and cerebrospinal uid (CSF), but with
positivity of antibodies against glutamic acid decarboxylase (GAD)
both in serum and CSF.
examination was negative for Campylobacter.
Peripheral facial nerve palsy appeared a week after admission;
after a few days it extended also to the right side causing bilateral
lagophthalmos. A brain MRI revealed no signicant abnormali-
ties.
Gait ataxia and rhinolalia showed an early improvement after
admission, while extrinsic ocular motility recovered slowly and
gradually after a few days. The follow-up performed bi-monthly
showed only the persistence of a modest left facial decit.

2. Case report 3. Immunological study

A 60-year-old man a week after complaining of a u-like syn-
drome, he developed acute neurological symptoms with ataxia and
rhinolalia, followed a day later by diplopia and numbness in the
hands and feet.
The neurological examination revealed bilateral oculomotion
defects, ptosis of the right eyelid, rhinolalia, ataxic broad-based
gait, and distal limb hypoesthesia. The strength was normal and
deep tendon reexes were absent. From the rst day, a therapy was
started with intravenous immunoglobulin 0.4 g/kg/die for 5 days,
with no benet.
A lumbar puncture showed a slight increase in CSF protein
(58 mg/dL), with negative polymerase chain reaction (PCR) test for
Corresponding author at: Department of Neurosciences, Neurology Unit,
Azienda Ospedaliero-Universitaria, Via Gramsci 14, 43126 Parma,
Italy. Tel.: +39 521704128.
E-mail address: vladimiro.pietrini@unipr.it (V. Pietrini).
Several assays were performed including: anti-nuclear antibod-
ies (ANA), anti-gliadin antibodies (AGA), anti-thyroid peroxidase
(TPO), antibodies against Borrelia burgdorferi, rheumatoid factor,
sedimentation rate, total complement and fractions, tumor mark-
ers (alpha-fetoprotein, CEA, CA 19.9, PSA, CA 15.3, CYFRA 21.1,
NSE), and antibodies against Mycoplasma pneumonia. All tests were
within the normal range.
Serum and CSF antibody tests against GQ1b, GM1, GD1a, GD1b,
and GM2 for both IgG class and IgM one were negative except for
IgM anti-GM1 antibodies in serum: 2391 OD (normal range: <50)
and in CSF: 240 OD (normal range: <50).
The serum anti-GAD 65 antibody test performed by enzyme-
linked immunosorbent assay (ELISA) at hospitalization was
positive: 33.8 IU/mL (normal range: <5 IU/mL).
The CSF anti-GAD 65 antibody test was also positive, with
increased intrathecal production: 1.67 (normal range: 0.71.3).
The serum anti-GAD 65 antibody test was 10.6 IU/mL after 7
months and 3.0 IU/mL after 16 months.

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http://dx.doi.org/10.1016/j.clineuro.2012.11.008

Please cite this article in press as: Pietrini V, et al. Miller Fisher syndrome with positivity of anti-GAD antibodies. Clin Neurol Neurosurg (2012),
http://dx.doi.org/10.1016/j.clineuro.2012.11.008
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Table 1
Electrophysiological ndings.
Nerves DML (ms) MNCV (m/s) CMAP (mV)
L Tibial 7 (nv < 5) 33 (nv > 42) 3 (nv > 3)
L Peroneal 4 38 (nv > 43) 4 (nv > 3)
L Median 4 (nv < 4.5) 46 (nv > 49) 7 (nv > 6)
L Sural
R Facial 4.2 (nv < 4) 0.8 (nv > 1.5)
L Facial 4 0.5
DML, distal motor latency; MNCV, motor nerve conduction velocity; CMAP, compound muscular action potential; SCV, sensory conduction velocity; SAP, sensory action
potential; RNS, repetitive nerve stimulation. R: right; L: left; NV: normal value; A W: A waves; F W: F waves.
To exclude the concomitant presence of type-1 diabetes
mellitus (DM1), we investigated islet cell antibodies (ICA) by
immunouorescent-antibody assay (IFA) and insulinoma antigen
2 (IA2) antibodies, which tested negative.
4. Electrophysiological study
The electroneurographic study at 3 weeks from onset of symp-
toms showed: a marked reduction of the amplitude of the sensory
action potentials (SAP) of sural and median nerves with a slight
reduction of conduction velocity (CV); reduced amplitude of com-
pound muscular action potential (CMAP) and CV of tibial nerves,
with increased F waves and distal motor latencies; and the presence
of waves. The facial nerve examination showed a bilateral reduction
of the CMAP recorded from different muscles. The study of single-
ber electromyography of the frontalis muscle was abnormal. The
blink reex showed normal early (R1) and late (R2) response laten-
cies with reduced amplitude (see Table 1).
In conclusion, the electrophysiological study showed motor and
sensory neuropathy, both with axial and cranial localization and
with neuromuscular junction involvement.
5. Discussion
MFS diagnosis is based on the presence of the clinical triad of
ataxia, ophthalmoplegia and areexia, along with insignicant limb
weakness [1].
MFS has long been associated in the acute phase with anti-
GQ1b antibodies in more than 90% of patients [1]; moreover,
anti-GQ1b antibodies proved to be implicated in the pathogenesis
of ophthalmoplegia [2,3], and, probably, of ataxia related to MFS.
A small proportion of MFS cases never test positive for anti-GQ1b
antibodies, although they are clinically indistinguishable from anti-
GQ1b-positive patients [4]. For these anti-GQ1b-negative cases, the
presence was assumed of different antibodies that could bind to
similar sites and cause the same transient damage as in the more
common cases [4]. Recently, IgG antibodies against GM1b, GD1c,
GalNAc-GM1b and ganglioside complexes were found to be sero-
logical markers of GQ1b-seronegative MFS [5]. Furthermore, some
anti-GQ1b-negative sera react with a mixture antigen consisting of
phosphatidic acid and GQ1b, or react with ganglioside complexes
containing of GQ1b or GT1a. Serum and CSF anti-GQ1b antibody
tests were negative in our patient. The ELISA assay for detection
of antibodies to four gangliosides was negative in our case except
for anti-GM1 IgM antibodies. We consider this latter nding not
specic for GBS according to the literature [6].
In animals and humans, anti-GQ1b antibodies can alter the
transmission of neuromuscular junctions at the pre- and postsy-
naptic levels [2]. Similar electrophysiological abnormalities were
reported in anti-GQ1b-negative cases [7].
Please cite this article in press as: Pietrini V, et al. Miller Fisher syndrome with positivity of anti-GAD antibodies. Clin Neurol Neurosurg (2012),
http://dx.doi.org/10.1016/j.clineuro.2012.11.008
F waves (ms; %) SCV (m/s) SAP (uV) RNS SF-EMG
(Jitter us)
62/75; 100%
F W Absent
A W Present
31/34 100% 34 (nv > 40) 1 (nv > 10)
25 (nv > 36) 2 (nv > 6)
3 Hz: Decr. 5%
30 Hz: No increment
54 33.4
blocks (nv < 40)
GAD is the rate-limiting enzyme for the synthesis of -
aminobutyric acid (GABA), the main inhibitory neurotransmitter
in the central nervous system. The enzyme is selectively expressed
in GABAergic neurons and in pancreatic -cells. Autoantibodies to
GAD are detected in about 80% of DM1 patients. High anti-GAD
antibody levels are present in many patients with stiff person syn-
drome (SPS), patients with late-onset cerebellar ataxia, and a few
patients with epilepsy and brainstem dysfunction [8].
Recent papers have emphasized that in neurological syndromes
associated with anti-GAD antibodies, the titers of these antibod-
ies should be very high, sometimes using them as a prerequisite
for evaluating case studies in a prospective and/or retrospective
manner [8]. In our view, this introduces a methodological bias,
reducing the chance of well-dened neurological syndromes asso-
ciated with low (but pathological) antibody titers and, especially,
with high/medium-sized titers.
In our case, the 33.8 IU/mL titer over a normal range of <5 IU/mL
must be considered clinically relevant, representing a seven-fold
increase. In the evaluation of neurological syndromes, it might be
more useful to consider the intrathecal synthesis of specic anti-
GAD antibodies [8]. In our case the antibody index of anti-GAD
had a pathological value of 1.67 (n.v. 0.71.3). We can exclude
that the elevation of anti-GAD antibodies could be due to unrec-
ognized DM1, given blood glucose levels in the normal range and
the negativity of ICA and IA2 antibodies. In addition, the likelihood
that anti-GAD antibodies were truly pathogenic in our patient was
increased by the progressively harmonious decline of their titers
in the less acute phase of the disease. As regards the pathogenetic
connection between anti-GAD-antibodies and MFS, in our case the
antibodies seemed to bind to the same structures involved in classic
MFS, i.e. neurons in the cerebellum and brainstem and in the synap-
tic endings of oculomotor and facial nerves. The presence of GAD
in the nerve endings of neuromuscular junctions has already been
reported [9]. Anti-GAD antibodies have been found in association
with LambertEaton myasthenic syndrome, a typical pathological
condition of neuromuscular junctions.
6. Conclusion
We think that the association found in our case between MFS
and the presence of anti-GAD antibodies in both serum and CSF
could be pathogenetically signicant. It could be useful to search for
the presence of anti-GAD antibodies in other cases with anti-GQ1b-
negative MFS to shed light on the rate of occurrence of this nding.
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Please cite this article in press as: Pietrini V, et al. Miller Fisher syndrome with positivity of anti-GAD antibodies. Clin Neurol Neurosurg (2012),
http://dx.doi.org/10.1016/j.clineuro.2012.11.008