Acute oculomotor impairment with anti-GQ1b IgG
due to central nervous system dysfunction
Elisa Candeloro a
Giovanni Piccolo a
Roberto Bergamaschi a
Alfredo Romania, b
Eleonora Gavazzi a
Maurizio Versino c
a Department of
Clinical Neurology and Special Therapies, IRCCS “C. Mondino
Institute of Neurology” Foundation,
b Evoked Potential
Laboratory, IRCCS “C. Mondino Institute of Neurology”
c Eye Movement
Laboratory, IRCCS “C. Mondino Institute of Neurology”
Reprint requests to: Dr Elisa Candeloro,
Fondazione Istituto Neurologico C. Mondino
Via Mondino, 2 - 27100 Pavia - Italy
Accepted for publication: September 28, 2005
We report the case of a patient with isolated central oculomotor impairment and anti-GQ1b antibody.
The patient was referred to us with acute vertical diplopia. The neurological examination revealed right internuclear ophthalmoplegia (INO), skew deviation and mild gait ataxia. Extensive laboratory analyses, CSF study, multimodal evoked potentials and brain MRI were normal. Eye movement recording showed saccade dysmetria in addition to the INO. The subjective visual vertical was abnormally tilted to the left.
The anti-GQ1b IgG antibody was detectable on serum DOT-BLOT.
The brainstem and cerebellar features of the oculomotor impairment suggested that in our patient the anti-GQ1b IgG antibody showed a preferential cross-reaction with central nervous system epitopes. This finding is at variance with previous reports on anti-GQ1b syndrome with acute ophthalmoplegia, all of which argue for a localization of GQ1b epitopes within the peripheral nervous system, even though, in the light of the description of the ocular motor disorder, a central involvement might have co-occurred in this case.
WORDS: acute ophthalmoplegia, anti-GQ1b IgG antibody, central nervous system, diplopia.
In 2001, Odaka et al. (1) recognized an entity, termed “anti-GQ1b IgG antibody syndrome”, that covers a broad clinical spectrum ranging from isolated acute ophthalmoparesis (AO) or ataxia, to Miller-Fisher syndrome (MFS), Bickerstaff’s brainstem encephalitis (BBE), and to cases in which MFS, BBE and acute Guillain-Barré syndrome (GBS) overlap (1); they also suggested that all these various illnesses share a common autoimmune pathogenesis.
In anti-GQ1b IgG antibody syndrome, AO is rare, presenting in 9% of patients in the largest reported series (1), and ophthalmoplegia may show a chronic or relapsing rather than an acute monophasic course (2,3).
In accordance with biochemical and immunohistochemical findings (4-6), it has been suggested that AO can be considered a mild or atypical form of MFS (4,7), which usually includes a “peripheral” oculomotor nerve dysfunction.
However, central oculomotor impairment was reported in a few MFS patients (8,9), and probably occurred in AO patients as well (7,10,11).
Here, we report the first patient with anti-GQ1b IgG antibody and acute diplopia whose clinical and neurophysiological features suggest central oculomotor impairment without peripheral nervous system involvement or consciousness disturbance.
A 26-year-old male complained of acute diplopia and slight unsteadiness in April
Twenty-eight months later he was still well, brain MRI was normal, and anti-GQ1b IgG antibody was no longer detectable.
This is the first report of acute isolated central oculomotor impairment with anti-GQ1b antibody. The patient, presenting neither a consciousness disturbance nor long tract signs, did not fulfil the diagnostic criteria for typical or atypical MFS, or the BBE diagnostic criteria as proposed by Odaka et al. (1). The patient instead presented brainstem and cerebellar oculomotor impairment without clinical or neurophysiological peripheral nervous system involvement.
The oculomotor abnormalities detected in our patient are in keeping with the hypothesis of a brainstem and, possibly, cerebellar dysfunction. The patient presented an abnormal subjective visual vertical, which suggests an imbalance along the otolith and/or the vertical semicircular canal pathways. This imbalance may be located somewhere between the vestibular nerve and the vestibular cortex (12). It seemed likely that our patient’s dysfunction was located within the brainstem: he presented, as mentioned, an abnormal subjective visual vertical without rotatory vertigo, but with both skew deviation and INO. Internuclear ophthalmoplegia is a classic brainstem sign caused by a medial longitudinal fasciculus lesion; moreover, our patient also showed saccade hypermetria, which is attributable to cerebellar vermis dysfunction.
The literature contains few descriptions of similar patients (10,11), but before the first report of anti-GQ1b antibody (13), Abad and Wolintz (10) reported a single case of post-infectious isolated gaze palsy. Slavin (11) described two patients presenting gaze palsy, without long tract signs or changes in mental status, that followed a viral disease. These patients recovered completely. The clinical features, unilateral gaze paresis and gaze-evoked nystagmus in one patient, and Parinaud’s syndrome in the other, suggested brainstem involvement.
The presence of anti-GQ1b antibody was reported in patients presenting with acute isolated post-infectious ophthalmoparesis (4,7,14). The ophthalmoparesis was peripheral in all of them, with the exception of two patients described by Yuki et al. in whom an additional central component might have superimposed (7).
Recently, Lyu and Chen (15) described three patients with multiple cranial neuropathy associated with anti-GQ1b antibody; all these patients presented with an oculomotor disorder, the description of which, in two of them, does not rule out possible CNS involvement.
Finally, Hamaguchi et al. (2) reported a patient with
anti-GQ1b syndrome who suffered three different relapses with different scenarios of central and peripheral nervous system involvement.
How the same antibody can produce a variety of clinical signs involving central and peripheral targets remains to be clarified. It has been shown in animal models that anti-GQ1b IgG antibody induces a massive increase in spontaneous quantal acetylcholine release by means of a complement-mediated alpha-latrotoxin-like effect (16). This results in a blocking of neuromuscular transmission and in a subsequent complement-dependent destruction of the motor nerve terminal.
In anti-GQ1b antibody syndrome with AO, single fibre electromyography showed that the neuromuscular transmission improvement paralleled the clinical recovery (17).
Latrotoxin, a potent neurotoxin from black widow spider venom, stimulates a massive release of neurotransmitters both at peripheral and at central nervous system level (18). Subtypes of calcium-independent receptor for alpha-latrotoxin (CIRL1 and CIRL3) are predominantly expressed in the brain (19). The fine specificity of anti-GQ1b IgG antibody in the peripheral nervous system (20) may also apply for preferential cross-reaction with structurally differing gangliosides in the central nervous system. In rats, GQ1b ganglioside is localized in cerebellar glomeruli (21), and anti-GQ1b IgG antibodies in sera from MFS patients bind to the molecular layer of the human cerebellum (22).
Accordingly, the clinical picture of our patient could be explained by the blocking of neural transmission and subsequent tissue damage that probably occur preferentially at a central synapse level.
Moreover, the biological features of anti-GQ1b IgG antibody may not only explain the variability, but also indicate a different pathophysiology of the clinical signs. More specifically, our patient presented with brainstem and cerebellar rather than with peripheral oculomotor signs; this finding is at variance with most of previous reports and it broadens the spectrum of anti-GQ1b associated syndrome with prevalent or isolated oculomotor signs.
Generally this syndrome has a benign prognosis and the most appropriate treatment is yet to be established. Intravenous high-dose immunoglobulin and plasmapheresis has been claimed to be effective (23,24) and steroid treatment is not recommended, as in GBS and in MFS (1,7). The favourable course of our patient might be due to a spontaneous remission.
In conclusion, testing for anti-GQ1b IgG should be performed even in patients presenting with isolated acute central oculomotor impairment without clinical or instrumental data suggesting other diagnoses.
1. Odaka M, Yuki N, Hirata K. Anti-GQ1b IgG antibody syndrome: clinical and immunological range. J Neurol Neurosurg Psychiatry 2001;70:50-55
2. Hamaguchi T, Yamaguchi K, Komai K et al. Recurrent anti-GQ1b IgG antibody syndrome showing different phenotypes in different periods. J Neurol Neurosurg Psychiatry 2003;74:1350
3. Reddel SW, Barnett MH, Yan WX, Halmagyi GM, Pollard JD. Chronic ophthamoplegia with anti-GQ1b antibody. Neurology 2000;54:1000-1002
4. Chiba A, Kusunoki S, Obata H, Machinami R, Kanazawa I. Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillan-Barré syndrome. Neurology 1993;43:1911-1917
5. Chiba A, Kusunoki S, Obata H, Machimani R, Kanazawa I. Ganglioside composition of the human cranial nerves, with special reference to pathophysiology of Miller Fisher syndrome. Brain Res 1997;745:32-36
6. Kusunoki S,
7. Yuki N, Odaka M, Hirata K. Acute ophthalmoparesis (without ataxia) associated with anti-GQ1b IgG antibody. Ophthalmology 2001;108:196-200
8. Meienberg O. Lesion site in Fisher’s syndrome. Arch Neurol 1984;41:250-251
9. Al-Din AN, Anderson M, Bickerstaff ER, Harvey I. Brainstem encephalitis and the syndrome of Miller Fisher: a clinical study. Brain 1982;105:481-495
10. Abad VC, Wolintz A. Bilateral horizontal gaze palsy [case report]. Ann Ophthalmol 1982;14:1046-1048
11. Slavin ML. Gaze palsy associated with viral syndrome [case report]. Am J Ophthalmol 1985;100:468-473
12. Brandt TH, Dieterich M. Central vestibular syndromes in roll, pitch and yaw planes: topographic diagnosis of brainstem disorders. Neuro-ophthalmology 1993;15:291-303
13. Chiba A, Kusunoki S, Shimizu T, Kanazawa I. Serum IgG antibody to ganglioside GQ1b is a possible marker of Miller Fisher syndrome. Ann Neurol 1992;31:677-679
14. Sakurai Y, Mannen T, Kusunoki S. Acute isolated ophthalmoplegia as a variant of Miller-Fisher syndrome [Letter]. Muscle Nerve 1998;21:1107
15. Lyu RK, Chen ST. Acute multiple cranial neuropathy: a variant of Guillan-Barré syndrome? Muscle Nerve 2004; 30:433-436
16. Bullens RW, O’Hanlon GM, Goodyear CS et al. Anti-GQ1b antibodies and evoked acetylcholine release at mouse motor endplates. Muscle Nerve 2000;23:1035-1043
17. Lo LY, Chan LL, Pan A, Ratnagopal P. Acute ophthalmoparesis in the anti-GQ1b antibody syndrome: electrophysiological evidence of neuromuscular transmission defect in orbicularis oculi. J Neurol Neurosurg Psychiatry 2003;75: 436-440
18. Scheer H, Madeddu L, Dozio N, Gatti G, Vicentini LM, Meldolesi J. Alpha latrotoxin of black spider venom: an interesting neurotoxin and a tool for investigating the process of neurotransmitter release. J Physiol 1984;79:216-221
19. Ichtchenko K, Bittner MA, Krasnoperov V. A novel ubiquitously expressed alpha-latrotoxin receptor is a member of the CIRL family of G-protein-coupled receptors. J Biol Chem 1999;274:5491-5498
20. Susuki K, Yuki N, Hirata K. Fine specificity of anti-GQ1b IgG and clinical features. J Neurol Sci 2001;185:5-9
21. Kotani M, Kawashima I, Ozawa H, Terashima T, Tai T. Immunohistochemical localization of major gangliosides in rat cerebellum. Proc Jpn Acad 1992;68:109-113
22. Kornberg AJ, Pestronk A, Blume GM, Lopate G, Yue J, Hahn A. Selective staining of the cerebellar molecular layer by serum IgG in Miller-Fisher and related syndromes. Neurology 1996;47:1317-1320
23. Yuki N. Acute paresis of extraocular muscles associated with IgG anti-GQ1b antibody. Ann Neurol 1996;39:668- 672
24. Kikuchi M, Tagawa Y, Saotome S et al. Acute ophthalmoparesis associated with IgG anti-GQ1b antibody subsequent to Streptococcus pyogenes infection. Eur J Paediatr Neurol 1997;1:47-48