Chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M paraprotein, cold agglutinins, and disialosyl antibodies presenting after <scp>COVID19 mRNA</scp> vaccination

A 70-year-old right-handed woman was referred for a 12-month history of sensory symptoms, weakness, and incoordination. Her symptoms started approximately 2 weeks after receiving her first dose of the mRNA COVID-19 vaccine. She described a gradual onset of paresthesias and numbness affecting her hands and feet, incoordination in her arms, and intermittent binocular diplopia. The symptoms progressed slowly over 4 months and plateaued only to start progressing again at 10 months. At 12 months, she was evaluated at our institution. She had bilateral esophoria with cross-cover testing. The cranial nerve exam was otherwise normal. She had mild distal weakness in the upper extremities with mild proximal weakness in the lower extremities. Reflexes were absent, and she had down-going plantar responses. Sensory examination showed a length-dependent reduction of pain and temperature sensation, including a shield-pattern on the chest. Vibration and joint position testing were mildly reduced at the great toes. There was no upper extremity dysmetria and her Romberg test was positive. Gait was mildly unsteady. She had a normal complete blood count, electrolytes, renal, liver, thyroid, and diabetes screening. Serum protein electrophoresis demonstrated an immunoglobulin (Ig) M kappa monoclonal gammopathy; IgM 489 mg/dL (normal 40–300 mg/dL), IgA 37 mg/dL (normal 60–420 mg/dL) and IgG 537 mg/dL (normal 680–1800 mg/dL). Nerve conduction studies demonstrated the absence of all sensory nerve responses with relatively preserved motor responses, without demyelinating features (Table 1). Needle electromyography was not performed. Magnetic resonance imaging of the brain and entire spine with gadolinium was unremarkable. Lumbar puncture showed a borderline elevated protein (45 mg/dL, normal 15–45 mg/dL) with normal glucose and without pleocytosis. Immunologic evaluation revealed positive disialosyl antibodies; qualitative line immunoassay signal intensity for anti-GQ1b was 7 (normal 0–5), and for anti-GD1b was 8 (normal 0–5). Subsequently, cold agglutinin testing that was positive, confirming the diagnosis of chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M paraprotein, cold agglutinins, and disialosyl antibodies (CANOMAD). There was no evidence of a hematologic abnormality based on bone marrow biopsy and whole-body PET scan. She was reassessed 2 months later and had worsening of her ataxia and sensory symptoms resulting in functional impairment. She had markedly reduced vibration in her feet, bilateral dysmetria in the arms and legs and a wide-based ataxic gait. She could no longer walk for longer than 10 min and required a four-wheel walker. Repeat nerve conduction studies were unchanged. She underwent treatment with intravenous immunoglobulin (IVIg) 2 g/kg divided over 5 days. She showed an excellent response with improved walking endurance of up to 30 min and no longer needed a walking aid. However, approximately 6 weeks later, her symptoms recurred requiring repeat IVIg treatment (1 g/kg). She has since been receiving IVIg 1 g/kg every 2 weeks, which has resulted in mild residual deficits in her gait, vibration in her feet, and dysmetria. CANOMAD is a rare, acquired neuropathy with a heterogeneous presentation with less than 100 cases reported in the literature.1 An IgM-antibody-mediated attack, followed by complement-mediated destruction of the nodal and paranodal structures at the dorsal root ganglia, roots, and nerves, results in a chronic sensory neuronopathy causing ataxia and ophthalmoparesis.1-3 However, there is considerable heterogeneity in the clinical presentation. In the largest series of CANOMAD, patients only 47% presented with ataxia and 13% with ophthalmoparesis.1 Only 7% of patients presented with weakness, but 40% eventually developed weakness during their disease.1 CANOMAD is associated with an IgM paraproteinemia and up to 38% of patients have an underlying hematologic malignancy; most commonly Waldenstrom macroglobulinemia (20%).1 There are no randomized controlled trials to help determine ideal treatment regimens for CANOMAD; however, data from the largest case series suggest that half of patients see improvement in their disease when treated with IVIg or rituximab-based regimens.1 Early descriptions of CANOMAD proposed a link between immunological triggers and the disease.2 CANOMAD has been reported in the context of a SARS-COV2 infection; however, the patient had known Waldenstrom macroglobulinemia.4 Our case adds to the literature of this rare disease by highlighting vaccination as a possible immunological trigger for CANOMAD. Although specific vaccines for COVID19 have been associated with acquired neuropathy, the mRNA vaccine our patient received has not been linked with acquired neuropathy.5 CANOMAD is an immune-mediated disease that may present after intercurrent illness. While this case highlights a possible novel association between this rare condition and COVID-19 vaccination, more research is needed to definitively determine causation. Benjamin Beland: Conceptualization; writing – original draft; writing – review and editing. Theodore Mobach: Conceptualization; writing – review and editing; supervision. The authors declare no conflicts of interest. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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