Chronic sensory ataxic neuropathy and ophthalmoplegia with oculomotor nerve hypertrophy associated with IgM antibodies against gangliosides containing disialosyl groups.

Abstract

Writer's cramp (n = 10) t 51-6 (9 0) 8-6 (3-9) 1-56 (0l10)*** 1-53 (0-09)*** 9-7 (1-1) ratios of the individual patients were not known, it is hazardous to assess rates of decline in a small cross sectional sample. The results raise some questions. Firstly, there was bilateral reduction of available striatal D2 receptors, whereas the symptoms were unilateral and there was no asymmetry between the hemispheres. Bilateral abnormalities in writer's cramp, have, however, also been found by others.' I This bilaterality probably only means that the abnormalities found are related to particular motor dysfunctions which pass undetected if not properly challenged, as shown by the fact that many patients develop writer's cramp on the left side, if they change to writing with the left hand. Accordingly, it is also not uncommon to find involvement of the left, or fingering hand, in musicians playing keyboards, guitars, or other stringed instruments.3 A second question is why the reduced availability of D2 receptors was not accompanied by parkinsonism in our patients. According to well known models of basal ganglia function, overactivity of the indirect striatopallidal pathway is usually associated with parkinsonism. Because D2 receptor stimulation inhibits the indirect pathway, by contrast with the Dl receptor driven direct pathway,4 the decreased striatal D2 receptor binding in writer's cramp indicates disinhibition of the indirect pathway which might be expected to be accompanied by parkinsonism. In line with this view, we found the mean [123I]IBZM ratio to be 1-43 in patients with definite hypokinetic-rigid symptoms due to multiple system atrophy or progressive supranuclear palsy,2 which is in the same range as the values obtained in most of the present patients with writer's cramp (1-27-1-59).Therefore, our finding is probably better explained by loss of D2 receptors on cholinergic striatal intemeurons rather than D2 receptors on striatal spiny output neurons. The number of D2 receptors on striatal cholinergic intemeurons is sufficient to account for the decreased density of D2 receptors in our patients.5 Furthermore, striatal cholinergic interneurons are highly represented in the sensorimotor part of the striatum and are predominantly innervated by fibres from the thalamus suggesting a feed forward modulation from thalamus to striatum.6 A dysfunction of such thalamostriatal sensorimotor function-caused by increased activity of striatal cholinergic intemeurons resulting from disinhibition due to D2 receptor loss-fits the suggestion that central sensory processing in dystonia is impaired.7 Our hypothesis that writer's cramp dystonia could be related to an increased activity of striatal cholinergic interneurons is also consistent with the increased density of striatal cholinergic intemeurons in dystonia after perinatal asphyxial injury,8 and with the well known efficacy of anticholinergic therapy in dystonia.

The Role of Glycosphinglipids in Neurological Disorders: Mechanisms of Immune Actiona

“…34 Chronic sensory ataxic neuropathy and ophthalmoplegia with oculomotor nerve hypertrophy: Disialogangliosides. 47 Sensory ataxic neuropathy: GQ1bα; 48 fucosyl‐GD1b and GD1b having blood‐group B (IgM). 33 Severe sensory ataxia: GD1a.…”

“…Chronic sensory ataxic neuropathy and ophthalmoplegia with oculomotor nerve hypertrophy: Disialogangliosides. 47…”

Chronic ataxic neuropathies associated with anti-GD1b IgM antibodies: response to IVIg therapy

“…Neuropathies associated with immunoglobulin M (IgM) antibodies against disialosyl residues have been defined1 2 3 4 5 6 7 8 as either sensory ataxic neuropathy associated with anti-GD1b IgM antibody,9 chronic sensory ataxic neuropathy associated with anti-disialosyl IgM antibodies, or chronic ataxic neuropathy involving ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies (CANOMAD) 10. The most prominent feature of these neuropathies is sensory ataxia with relatively well-preserved muscle strength and small-fibre sensation.…”

Neuropathology of paraneoplastic neuropathy with anti‐disialosyl antibody

“…In the biopsy specimen, a decrease in large myelinated fibers was not obvious in the sural nerve. Several studies have shown loss of large myelinated fibers of the sural nerve in the neuropathy associated with anti‐disialosyl IgM antibodies, but the biopsy in these cases was performed some 6–25 years after onset 5, 6, 15, 17, 19, 21, 23. A decrease in larger myelinated fibers might therefore be prominent only at such a chronic stage.…”

“…Neuropathies associated with immunoglobulin M (IgM) antibodies against disialosyl residues have been reported1, 3–6, 12, 13, 15, 16, 19, 21, 23 as a “sensory ataxic neuropathy associated with anti GD1b IgM antibody,”17 a “chronic sensory ataxic neuropathy with anti‐disialosyl IgM antibodies,” or a “chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies (CANOMAD).”22 The most prominent feature of these neuropathies is sensory ataxia with relative preservation of muscle strength and small‐fiber sensation. The patients in these cases had IgM antibodies that reacted with GD1b containing a NeuNAc(α2‐8)NeuNAc(α2‐3)Gal epitope localized on the cell bodies of human dorsal root ganglia 8, 10.…”