CANOMAD: a neurological monoclonal gammopathy of clinical significance that benefits from B-cell–targeted therapies

Abstract

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular and/or bulbar motor weakness, in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurological symptoms. Main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia) (n=45, 100%), motor weakness (n=18, 40%), ophthalmoplegia (n=20, 45%) and bulbar symptoms (n=6, 13%). Forty five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiological studies showed a demyelinating or axonal pattern in respectively 60 and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40). Overt hematologic malignancies were diagnosed in 16 patients (36%), most frequently Waldenström macroglobulinemia (n=9, 20%). Forty-one patients (91%) required treatment for CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with respectively 53 and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line and rituximab-based regimens for second-line treatment. These compiling data argue for CANOMAD to be included in neurological monoclonal gammopathy of clinical significance.

CANOMAD unmasked by COVID‐19 in a man with Waldenström's macroglobulinaemia

“…However, a rigid interpretation of this pathway would only result in testing for ganglioside antibodies alongside anti-MAG antibodies in patients demonstrating conduction slowing/demyelination on electrophysiological testing. Findings from a recent large study of 45 patients with CANOMAD revealed a demyelinating pattern in 60%, with predominantly axonal features in 27% [3].…”

“…Ataxic neuropathy is frequently the dominant symptom, potentially causing severe disability. Disease trajectory is variable, typically extending over decades, with progression in two‐thirds and a third relapsing‐remitting [ 3 ]. Misdiagnosis is common, in part because fewer than half of the patients exhibit the full spectrum of clinical features, ultimately delaying appropriate treatment.…”

“…However, a rigid interpretation of this pathway would only result in testing for ganglioside antibodies alongside anti‐MAG antibodies in patients demonstrating conduction slowing/demyelination on electrophysiological testing. Findings from a recent large study of 45 patients with CANOMAD revealed a demyelinating pattern in 60%, with predominantly axonal features in 27% [ 3 ]. Therefore, it is important not to rely solely on the reported pattern of electrophysiological abnormality, and maintain a high index of suspicion in cases exhibiting the aforementioned neurological phenotype.…”

“…There remains a lack of evidence‐base for the treatment of CANOMAD. IVIg and rituximab are reportedly most efficacious, whereas corticosteroids and other forms of immunosuppression have little or unfavourable impact [ 3 ]. In this case, rituximab—administered for the haematological malignancy and associated neuropathy—likely had a stabilising effect on the neuropathy, in keeping with previously described cases [ 3 , 12 ].…”

Waldenström’s Macroglobulinemia: An Exploration into the Pathology and Diagnosis of a Complex B-Cell Malignancy

“…IgM disialosyl antibodies could be associated with CANOMAD: Chronic Ataxic Neuropathy with Ophthalmoplegia, M-protein, cold Agglutinins and Disialosyl ganglioside (IgM Anti-GD1b/ GT1b/GQ1b) antibodies. 32 In CANOMAD, nerve conduction tests show a mixed pattern of axonal loss and demyelinating features. 30-40% of IgM-related demyelinating neuropathies have no identifiable antibodies.…”