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I read with interest the review by Odaka et al 1 of the range of clinical disorders manifesting in patients with raised anti-GQ1b IgG antibodies. Their patients were classified into Miller Fisher syndrome, Bickerstaff's brain stem encephalitis, acute ophthalmoparesis without ataxia, Guillain-Barré syndrome, and “unclassified”. The last group included patients who all had external ophthalmoplegia and normal tendon reflexes, and also varying degrees of limb, facial, and bulbar weakness. I have recently encountered a patient who developed an acute, sensory polyneuropathy in association with raised anti-GQ1b IgG antibodies, whose clinical features differ from the 194 patients described in their series.
A previously well 35 year old man had an episode of sore throat and dry cough, with associated myalgia and fever, in May 2000. Two weeks later, he developed tingling paraesthesia first in his feet, spreading up to his knees, and then in both hands. He found it difficult to distinguish where the ground was beneath his feet because of reduced sensation. One week into this illness, he developed partial drooping of his right eyelid. He had no symptoms of weakness or double vision. On examination 3 days later, he had a partial right ptosis, but eye movements were normal and he did not report diplopia. Muscle power and tendon reflexes were normal in all four limbs. He had a rather deliberate gait because of very mild sensory ataxia with reduced sensation to pain, light touch, and vibration sensation in both legs, to the level of the knees. Joint position sense was impaired in the toes but normal in the fingers.
Nerve conduction studies 3 weeks into his neurological illness showed normal distal motor latencies, proximal conduction velocities, and F wave latencies in all four limbs. All sensory nerve action potentials were absent. Protein in CSF was raised at 0.7 g/l (acellular sample). Coxsackie B IgG antibodies were raised at 1:64. Antiganglioside antibody assays showed raised IgG titres to GQ1b (1:8000), GD1b (1:11000), and GT1b (1:2200).Over the course of the next 2 weeks he improved without treatment, achieving full recovery with no residual symptoms or signs.
The lack of external ophthalmoplegia and ataxia was only encountered in patients classified as Guillain-Barré syndrome in the series by Odakaet al,1 all of whom had limb weakness and reduced or absent reflexes. The electrophysiological findings in this patient were not compatible with criteria for demyelinating or axonal Guillain-Barré syndrome, but repeated studies can rarely be normal.2 Electrophysiological studies on patients with Guillain-Barré syndrome with ophthalmoplegia and positive anti-GQ1b antibody titres have shown marked attenuation or absence of sensory nerve action potentials, suggesting that anti-GQ1b antibodies may be particularly involved in sensory nerve conduction failure.3
A recent report of eight cases of sensory Guillain-Barré syndrome has highlighted the existence of this variant.4 Two of these patients had normal motor nerve conduction studies, one of whom had essentially normal tendon reflexes. Not all of these patients were tested for antiganglisoide antibodies.
The GQ1b ganglioside is present in both sensory and motor nerves, including oculomotor nerves,5 and the range of disease associated with anti-GQ1b antibodies could theoretically involve dysfunction in any one or more of these types of nerves in varying degrees. If the screening of antiganglioside antibodies is extended to all patients with Guillain-Barré syndrome and its variants (with or without ocular signs) in a large series, then the clinical range associated with anti-GQ1b antibodies will no doubt expand to include more patients without marked ataxia or external ophthalmoplegia, as in this case.
I thank Dr Hugh Willison, Southern General Hospital, Glasgow, for performing antiganglioside antibody assays, and for helpful comments.
Odaka and Yuki reply:
Maddison considered that clinical features of his patient were similar to those of “sensory Guillain-Barré syndrome”, as proposed by Oh et al.1-1 All of the patients of Oh et al had electrophysiological evidence of demyelination in at least two sensory nerves. By contrast, no evidence of demyelination in sensory nerves was shown in his patient. To produce the evidence, Maddison should have repeatedly performed sensory nerve conduction studies during the convalescent phase. Because sensory nerve action potentials were absent in his patient, the “syndrome of acute sensory neuropathy” as proposed by Windebank et al 1-2may be the diagnosis.
We earlier reported on a patient with a relapsing form of the acute sensory neuropathy syndrome.1-3 The patient rapidly developed marked sensory ataxia without ophthalmoplegia and limb weakness after an upper respiratory tract infection. The symptoms reached their maximum in a few days, followed by subsequent improvement over a few weeks. However, unsteady gait remained as a chronic deficit. Stepwise progression of his symptoms occurred over 15 years with 10 similar relapses. Sensory nerve conduction studies showed the absence of action potentials, and sural nerve biopsy showed the marked loss of large myelinated fibres. The patient's serum had an extremely high titre of an IgM monoclonal antibody directed against b series gangliosides GD2, GD1b, GT1b, and GQ1b. His IgM reacted neither with GD3 nor with GT1a. An absorption study showed that the anti-GQ1b IgM antibody cross reacted with GD2, GD1b, and GT1b.1-4 The common sugar structure (NeuAc-α2–8-NeuAc α2–3 (GalNAc β1–4) Gal β) seems to be the binding site of the IgM antibody. Interestingly, serum IgG from the patient of Maddison reacted with GD1b, GT1b, and GQ1b, although whether his IgG had antibody activity against GD2 and GD3 was not shown. An absorption study would clarify whether his IgG reacted with a disialosyl residue linked to the internal galactose common to b series gangliosides. An immunohistochemical study showed localisation of GD1b in the neurons of the human dorsal ganglion. GD1b is also localised in the large neurons of the rabbit dorsal root ganglion, and Kusunoki et al 1-5 succeeded in the development of sensory ataxic neuropathy by sensitisation with GD1b. Autoantibody to b series gangliosides including GD1b may function in the development of acute sensory ataxic neuropathy in some patients.
Anti-GQ1b IgG antibody from patients with Miller Fisher syndrome cross reacts with GT1a. GT1a has a disialosyl residue linked to the external galactose common to GQ1b, and this may be the binding site of the autoantibody. We investigated the fine specificity of anti-GQ1b IgG antibody in serum samples from 82 patients: 56 with Miller Fisher syndrome, 11 with Guillain-Barré syndrome, 13 with Bickerstaff's brain stem encephalitis, and two with acute ophthalmoparesis. External ophthalmoplegia was present in all of these patients. Anti-GQ1b IgG antibodies were absorbed by GT1a in 80 (98%) of the 82 serum samples, by GD1b in 11 (13%), and by the other b series gangliosides GD3, GD2, or GT1b in 24 (29%). The most frequent pattern of fine specificity was the cross reaction with GT1a alone, seen in 56 (68%) samples. By contrast, we recently noted that some patients with the “ataxic form of Guillain-Barré syndrome” showed no or minimal external ophthalmoplegia but had anti-GQ1b IgG antibody. Anti-GQ1b IgG antibody from the patients, as well as those with Miller Fisher syndrome, were absorbed by GT1a. The finding that ataxic Guillain-Barré syndrome and Miller Fisher syndrome have in common an autoantibody with the same fine specificity suggests that they form a continuous range. We should not have used the term “anti-GQ1b IgG antibody syndrome”, but rather, “anti-GQ1b/GT1a IgG antibody syndrome”, which includes Miller Fisher syndrome, Guillain-Barré syndrome with ophthalmoplegia, Bickerstaff's brain stem encephalitis, acute ophthalmoparesis without ataxia, and the ataxic form of Guillain-Barré syndrome. Maddison did not show that his patient's IgG had antibody activity against GT1a, but his case could be categorised as the syndrome of acute sensory neuropathy if the patient's IgG did not react with GT1a.
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