IgG4-related disease: neurologic manifestations
Nov. 29, 2022
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The author describes the clinical, electrophysiological, and pathological phenotype of neuropathies associated with anti-GD1b antibodies, frequently manifested by prominent ataxia. These may arise as acute postinfectious syndromes or as chronic paraproteinemia-associated syndromes. Antibodies that bind to complexes of GD1b with GD1a, but not to either ganglioside alone, have been identified in a proportion of Guillain Barré syndrome sera, underlining the complexity of how antibodies are able to sense their target antigens in neural membranes. Some patients have been successfully treated with intravenous immunoglobulin and rituximab.
• Anti-GD1b IgG or IgM antibodies are associated with acute or chronic ataxic neuropathy syndromes respectively.
• In patients with chronic ataxic neuropathy and IgM paraproteinaemia, screening for CANOMAD should be considered.
• CANOMAD may exist in formes frustes where not all clinical or laboratory components are manifested.
• Sensory ataxic variants of Guillain Barré syndrome are often associated with anti-GD1b IgG antibodies.
• Identification of syndromes associated with an anti-GD1b antibody biomarker should alert clinicians to a potentially treatable disorder.
In the early 1980s many clinical and serological studies started focusing on peripheral neuropathy syndromes associated with IgM paraproteinemia. Paraproteins have also been referred to as M-proteins or (benign) monoclonal gammopathies of undetermined significance (MGUS). The specificities of these paraproteins were almost invariably found to be directed to carbohydrate determinants present on different glycoproteins and glycolipids distributed in neural tissue. The first to be identified were myelin-associated glycoprotein (MAG) and structurally related glucuronic acid-containing acidic glycosphingolipids (33).
In 1985 a case of IgM paraproteinemic neuropathy in which the paraprotein reacted with NeuNAc(alpha2-8)NeuNAc(alpha2-3) configured disialylated gangliosides including GD1b, GD3, GD2, and GT1a, GT1b, and GQ1b was reported (14). Following this report, several other cases similarly characterized by a chronic sensory ataxic neuropathy were reported in the early 1990s (01; 08; 28; 52; 54; 47; 10; 11). A series of 18 cases was reported in 2001 that describes the syndrome more completely (46). It is now apparent that this syndrome represents a relatively pure clinical-serological phenotype, dominated by sensory ataxia without functionally substantial limb weakness in most cases. Terminologically, these cases have been referred to variously as sensory neuropathy, sensory ataxic neuropathy, peripheral neuropathy, or ataxic neuropathy with anti-GD1b, anti-disialosyl, or anti-B series ganglioside antibodies. The rarity of this syndrome is highlighted by a screening study of 101 MGUS-associated neuropathy cases in which only 3 had anti-GD1b IgM antibodies, compared with 52 in the same series who were anti-MAG positive (41).
In some cases the IgM paraprotein also has cold agglutinating activity with anti-Pr specificity (01; 47; 10). In other cases craniobulbar motor involvement, including ophthalmoplegia, may also be present (13; 10). To reflect this, in 1996 the acronym CANOMAD was coined to encompass this phenotype, chronic ataxic neuropathy with ophthalmoplegia, M-protein, agglutination and disialosyl antibodies (45). Although this acronym is useful as an aide memoir when considering potential cases, it should be appreciated that not all cases exhibit the full spectrum of clinical features. Nevertheless, the association between ataxia and anti-GD1b antibody is strong (38). In a Japanese series of 5 cases of sensory ataxic neuropathy with anti-GD1b antibodies and IgM paraproteinemia, all patients had severe sensory ataxia and areflexia, but only 1 of the 5 cases manifested a transient diplopia on lateral gaze and 2 of the 5 cases had cold agglutinins (39). In contrast, 2 cases reported as part of a long-term follow-up of paraproteinemic neuropathy cases had all the features of CANOMAD (31).
In a large series of 18 cases (46), the syndrome was described as a chronic sensory ataxic neuropathy with anti-disialosyl antibodies, and cases showed remarkable clinical homogeneity, as described below.
Acute phase anti-GD1b IgG antibodies have been identified in isolated patients with acute sensory neuropathies, acute ataxic neuropathies, or both, without limb weakness, which is considered a forme fruste or regional variant of Guillain Barré syndrome (48; 53; 50). Some patients with Miller Fisher syndrome (MFS or Fisher syndrome) also have anti-GD1b antibodies by virtue of their cross-reactivity with anti-GQ1b/GT1a antibodies, which are universally found in this syndrome (04; 48; 39). In addition, it has been observed that GD1b antibodies are statistically associated with sensory symptoms in Guillain Barré syndrome (44) and with ataxia (18). A clinical and serological review of patients with ataxic Guillain Barré syndrome and acute sensory ataxia has concluded that this clinical syndrome represents an incomplete forme fruste of Miller Fisher syndrome (15). Indeed, the long-standing concept of a spectrum between Miller Fisher syndrome and CANOMAD, linked through anti-disialosyl antibodies, has been highlighted (55). Antibodies to GD1b/GD1a ganglioside complexes are present in a proportion of Guillain-Barré syndrome cases (19). Thus, the spectrum of sensory neuropathies associated with anti-GD1b antibodies has expanded to both chronic and acute disorders, the former being associated with IgM paraproteins and the latter with acute phase, transient IgG antibodies. This topic focuses on the IgM paraproteinemia-associated syndromes.
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